Computational immunology

From Wikipedia, the free encyclopedia

 

In academia, computational immunology is a field of science that encompasses high-throughput genomic and bioinformatics approaches to immunology. The field's main aim is to convert immunological data into computational problems, solve these problems using mathematical and computational approaches and then convert these results into immunologically meaningful interpretations.

Introduction

The immune system is a complex system of the human body and understanding it is one of the most challenging topics in biology. Immunology research is important for understanding the mechanisms underlying the defense of human body and to develop drugs for immunological diseases and maintain health. Recent findings in genomic and proteomic technologies have transformed the immunology research drastically. Sequencing of the human and other model organism genomes has produced increasingly large volumes of data relevant to immunology research and at the same time huge amounts of functional and clinical data are being reported in the scientific literature and stored in clinical records. Recent advances in bioinformatics or computational biology were helpful to understand and organize these large scale data and gave rise to new area that is called Computational immunology or immunoinformatics. 

Computational immunology is a branch of bioinformatics and it is based on similar concepts and tools, such as sequence alignment and protein structure prediction tools. Immunomics is a discipline like genomics and proteomics. It is a science, which specifically combines Immunology with computer science, mathematics, chemistry, and biochemistry for large-scale analysis of immune system functions. It aims to study the complex protein–protein interactions and networks and allows a better understanding of immune responses and their role during normal, diseased and reconstitution states. Computational immunology is a part of immunomics, which is focused on analyzing large scale experimental data.

History

Computational immunology began over 90 years ago with the theoretic modeling of malaria epidemiology. At that time, the emphasis was on the use of mathematics to guide the study of disease transmission. Since then, the field has expanded to cover all other aspects of immune system processes and diseases.

Immunological database

After the recent advances in sequencing and proteomics technology, there have been many fold increase in generation of molecular and immunological data. The data are so diverse that they can be categorized in different databases according to their use in the research. Until now there are total 31 different immunological databases noted in the Nucleic Acids Research (NAR) Database Collection, which are given in the following table, together with some more immune related databases. The information given in the table is taken from the database descriptions in NAR Database Collection. 

Database	Description
ALPSbase	Autoimmune lymphoproliferative syndrome database
AntigenDB	Sequence, structure, and other data on pathogen antigens.
AntiJen	Quantitative binding data for peptides and proteins of immunological interest.
BCIpep	This database stores information of all experimentally determined B-cell epitopes of antigenic proteins. This is a curated database where detailed information about the epitopes are collected and compiled from published literature and existing databases. It covers a wide range of pathogenic organisms like virus, bacteria, protozoa and fungi. Each entry in database provides full information about a B-cell epitope that includes amino acid sequences, source of the antigenic protein, immunogenicity, model organism and antibody generation/neutralization test.
dbMHC	dbMHC provides access to HLA sequences, tools to support genetic testing of HLA loci, HLA allele and haplotype frequencies of over 90 populations worldwide, as well as clinical datasets on hematopoietic stem cell transplantation, and insulin dependent diabetes mellitus (IDDM), Rheumatoid Arthritis (RA), Narcolepsy and Spondyloarthropathy. For more information go to this link http://www.oxfordjournals.org/nar/database/summary/604
DIGIT	Database of ImmunoGlobulin sequences and Integrated Tools.
FIMM	FIMM is an integrated database of functional molecular immunology that focuses on the T-cell response to disease-specific antigens. FIMM provides fully referenced information integrated with data retrieval and sequence analysis tools on HLA, peptides, T-cell epitopes, antigens, diseases and constitutes one backbone of future computational immunology research. Antigen protein data have been enriched with more than 27,000 sequences derived from the non-redundant SwissProt-TREMBL-TREMBL_NEW (SPTR) database of antigens similar or related FIMM antigens across various species to facilitate a comprehensive analysis of conserved or variable T-cell epitopes.
GPX-Macrophage Expression Atlas	The GPX Macrophage Expression Atlas (GPX-MEA) is an online resource for expression based studies of a range of macrophage cell types following treatment with pathogens and immune modulators. GPX Macrophage Expression Atlas (GPX-MEA) follows the MIAME standard and includes an objective quality score with each experiment. It places special emphasis on rigorously capturing the experimental design and enables the statistical analysis of expression data from different micro-array experiments. This is the first example of a focussed macrophage gene expression database that allows efficient identification of transcriptional patterns, which provide novel insights into biology of this cell system.
HaptenDB	It is a comprehensive database of hapten molecules. This is a curated database where information is collected and compiled from published literature and web resources. Presently database has more than 1700 entries where each entry provides comprehensive detail about a hapten molecule that includes: i) nature of the hapten; ii) methods of anti- hapten antibody production; iii) information about carrier protein; iv) coupling method; v) assay method (used for characterization) and vi) specificities of antibodies. The Haptendb covers wide array of haptens ranging from antibiotics of biomedical importance to pesticides. This database will be very useful for studying the serological reactions and production of antibodies.
HPTAA	HPTAA is a database of potential tumor-associated antigens that uses expression data from various expression platforms, including carefully chosen publicly available microarray expression data, GEO SAGE data and Unigene expression data.
IEDB-3D	Structural data within the Immune Epitope Database.
IL2Rgbase	X-linked severe combined immunodeficiency mutations.
IMGT	IMGT is an integrated knowledge resource specialized in IG, TR, MHC, IG superfamily, MHC superfamily and related proteins of the immune system of human and other vertebrate species. IMGTW comprises 6 databases, 15 on-line tools for sequence, gene and 3D structure analysis, and more than 10,000 pages of resources Web. Data standardization, based on IMGT-ONTOLOGY, has been approved by WHO/IUIS.
IMGT_GENE-DB	IMGT/GENE-DB is the IMGT® comprehensive genome database for immunoglobulins (IG) and T cell receptors (TR) genes from human and mouse, and, in development, from other vertebrate species (e.g. rat). IMGT/GENE-DB is part of IMGT®, the international ImMunoGeneTics information system®, the high-quality integrated knowledge resource specialized in IG, TR, major histocompatibility complex (MHC) of human and other vertebrate species, and related proteins of the immune system (RPI) that belong to the immunoglobulin superfamily (IgSF) and to the MHC superfamily (MhcSF).
IMGT/HLA	There are currently over 1600 officially recognised HLA alleles and these sequences are made available to the scientific community through the IMGT/HLA database. In 1998, the IMGT/HLA database was publicly released. Since this time, the database has grown and is the primary source of information for the study of sequences of the human major histocompatibility complex. The initial release of the database contained allele reports, alignment tools, submission tools as well as detailed descriptions of the source cells. The database is updated quarterly with all the new and confirmatory sequences submitted to the WHO Nomenclature Committee and on average an additional 75 new and confirmatory sequences are included in each quarterly release. The IMGT/HLA database provides a centralized resource for everybody interested, either centrally or peripherally, in the HLA system.
IMGT/LIGM-DB	IMGT/LIGM-DB is the IMGT® comprehensive database of immunoglobulin (IG) and T cell receptor (TR) nucleotide sequences, from human and other vertebrate species, with translation for fully annotated sequences, created in 1989 by LIGM http://www.imgt.org/textes/IMGTinformation/LIGM.html), Montpellier, France, on the Web since July 1995. IMGT/LIGM-DB is the first and the largest database of IMGT®, the international ImMunoGeneTics information system® , the high-quality integrated knowledge resource specialized in IG, TR, major histocompatibility complex (MHC) of human and other vertebrate species, and related proteins of the immune system (RPI) that belong to the immunoglobulin superfamily (IgSF) and to the MHC superfamily (MhcSF). IMGT/LIGM-DB sequence data are identified by the EMBL/GenBank/DDBJ accession number. The unique source of data for IMGT/LIGM-DB is EMBL which shares data with GenBank and DDBJ.
Interferon Stimulated Gene Database	Interferons (IFN) are a family of multifunctional cytokines that activate transcription of a subset of genes. The gene products induced by IFN are responsible for the antiviral, antiproliferative and immunomodulatory properties of this cytokine. In order to obtain a more comprehensive understanding of the genes regulated by IFNs we have used different microarray formats to identify over 400 interferon stimulated genes (ISG). To facilitate the dissemination of this data we have compiled a database comprising the ISGs assigned into functional categories. The database is fully searchable and contains links to sequence and Unigene information. The database and the array data are accessible via the World Wide Web at (http://www.lerner.ccf.org/labs/williams/ ). We intend to add published ISG-sequences and those discovered by further transcript profiling to the database to eventually compile a complete list of ISGs.
IPD-ESTDAB	The Immuno Polymorphism Database (IPD) is a set of specialist databases related to the study of polymorphic genes in the immune system. IPD-ESTDAB is a database of immunologically characterised melanoma cell lines. The database works in conjunction with the European Searchable Tumour Cell Line Database (ESTDAB) cell bank, which is housed in TÜbingen, Germany and provides immunologically characterised tumour cells.
IPD-HPA - Human Platelet Antigens	Human platelet antigens are alloantigens expressed only on platelets, specifically on platelet membrane glycoproteins. These platelet-specific antigens are immunogenic and can result in pathological reactions to transfusion therapy. The IPD-HPA section contains nomenclature information and additional background material about Human platelet antigen. The different genes in the HPA system have not been sequenced to the same level as some of the other projects and so currently only single nucleotide polymorphisms (SNP) are used to determine alleles. This information is presented in a grid of SNP for each gene The IPD and HPA nomenclature committee hope to expand this to provide full sequence alignments when possible.
IPD-KIR - Killer-cell Immunoglobulin-like Receptors	The Killer-cell Immunoglobulin-like Receptors (KIR) are members of the immunoglobulin super family (IgSF) formerly called Killer-cell Inhibitory Receptors. KIRs have been shown to be highly polymorphic both at the allelic and haplotypic levels. They are composed of two or three Ig-domains, a transmembrane region and cytoplasmic tail, which can in turn be short (activatory) or long (inhibitory). The Leukocyte Receptor Complex (LRC), which encodes KIR genes, has been shown to be polymorphic, polygenic and complex in a manner similar to the MHC. The IPD-KIR Sequence Database contains the most up to date nomenclature and sequence alignments.
IPD-MHC	The MHC sequences of many different species have been reported, along with different nomenclature systems used in the naming and identification of new genes and alleles in each species. The sequences of the major histocompatibility complex from number of different species are highly conserved between species. By bringing the work of different nomenclature committees and the sequences of different species together it is hoped to provide a central resource that will facilitate further research on the MHC of each species and on their comparison. The first release of the IPD-MHC database involved the work of groups specialising in non-human primates, canines (DLA) and felines (FLA) and incorporated all data previously available in the IMGT/MHC database. This release included data from five species of ape, sixteen species of new world monkey, seventeen species of old world monkey, as well as data on different canines and felines. Since the first release, sequences from cattle (BoLA), swine (SLA), and rats (RT1) have been added and the work to include MHC sequences from chickens, horses (ELA) is still going on.
MHCBN	MHCBN is a comprehensive database comprising over 23000 peptides sequences, whose binding affinity with MHC or TAP molecules has been assayed experimentally. It is a curated database where entries are compiled from published literature and public databases. Each entry of the database provides full information like (sequence, its MHC or TAP binding specificity, source protein) about peptide whose binding affinity (IC50) and T cell activity is experimentally determined. MHCBN has number of web-based tools for the analysis and retrieval of information. All database entries are hyperlinked to major databases like SWISS-PROT, PDB, IMGT/HLA-DB, PubMed and OMIM to provide the information beyond the scope of MHCBN. Current version of MHCBN contains 1053 entries of TAP binding peptides. The information about the diseases associated with various MHC alleles is also included in this version.
MHCPEP	This database contains list of MHC-binding peptides.
MPID-T2	MPID-T2 (https://web.archive.org/web/20120902154345/http://biolinfo.org/mpid-t2/) is a highly curated database for sequence-structure-function information on MHC-peptide interactions. It contains all structures of major histocompatibility complex proteins (MHC) containing bound peptides, with emphasis on the structural characterization of these complexes. Database entries have been grouped into fully referenced redundant and non-redundant categories. The MHC-peptide interactions have been presented in terms of a set of sequence and structural parameters representative of molecular recognition. MPID will facilitate the development of algorithms to predict whether a query peptide sequence will bind to a specific MHC allele. MPID data has been sorted primarily on the basis of MHC Class, followed by organism (MHC source), next by allele type and finally by the length of peptide in the binding groove (peptide residues within 5 Å of the MHC). Data on inter-molecular hydrogen bonds, gap volume and gap index available in MPID are pre-computed and the interface area due to complex formation is calculated based on accessible surface area calculations. The available MHC-peptide databases have addressed sequence information as well as binding (or the lack thereof) of peptide sequences.
MUGEN Mouse Database	Murine models of immune processes and immunological diseases.
Protegen	Protective antigen database and analysis system.
SuperHapten	SuperHapten is a manually curated hapten database integrating information from literature and web resources. The current version of the database compiles 2D/3D structures, physicochemical properties and references for about 7,500 haptens and 25,000 synonyms. The commercial availability is documented for about 6,300 haptens and 450 related antibodies, enabling experimental approaches on cross-reactivity. The haptens are classified regarding their origin: pesticides, herbicides, insecticides, drugs, natural compounds, etc. Queries allow identification of haptens and associated antibodies according to functional class, carrier protein, chemical scaffold, composition or structural similarity.
The Immune Epitope Database (IEDB)	The Immune Epitope Database (IEDB, www.iedb.org), provides a catalog of experimentally characterized B and T cell epitopes, as well as data on MHC binding and MHC ligand elution experiments. The database represents the molecular structures recognized by adaptive immune receptors and the experimental contexts in which these molecules were determined to be immune epitopes. Epitopes recognized in humans, non-human primates, rodents, pigs, cats and all other tested species are included. Both positive and negative experimental results are captured. Over the course of four years, the data from 180,978 experiments were curated manually from the literature, covering about 99% of all publicly available information on peptide epitopes mapped in infectious agents (excluding HIV) and 93% of those mapped in allergens.
TmaDB[permanent dead link]	To analyse TMA output a relational database (known as TmaDB) has been developed to collate all aspects of information relating to TMAs. These data include the TMA construction protocol, experimental protocol and results from the various immunocytological and histochemical staining experiments including the scanned images for each of the TMA cores. Furthermore, the database contains pathological information associated with each of the specimens on the TMA slide, the location of the various TMAs and the individual specimen blocks (from which cores were taken) in the laboratory and their current status. TmaDB has been designed to incorporate and extend many of the published common data elements and the XML format for TMA experiments and is therefore compatible with the TMA data exchange specifications developed by the Association for Pathology Informatics community.
VBASE2	VBASE2 is an integrative database of germ-line V genes from the immunoglobulin loci of human and mouse. It presents V gene sequences from the EMBL database and Ensembl together with the corresponding links to the source data. The VBASE2 dataset is generated in an automatic process based on a BLAST search of V genes against EMBL and the Ensembl dataset. The BLAST hits are evaluated with the DNAPLOT program, which allows immunoglobulin sequence alignment and comparison, RSS recognition and analysis of the V(D)J-rearrangements. As a result of the BLAST hit evaluation, the VBASE2 entries are classified into 3 different classes: class 1 holds sequences for which a genomic reference and a rearranged sequence is known. Class 2 contains sequences, which have not been found in a rearrangement, thus lacking evidence of functionality. Class 3 contains sequences which have been found in different V(D)J rearrangements but lack a genomic reference. All VBASE2 sequences are compared with the datasets from the VBASE-, IMGT- and KABAT-databases (latest published versions), and the respective references are provided in each VBASE2 sequence entry. The VBASE2 database can be accessed by either a text based query form or by a sequence alignment with the DNAPLOT program. A DAS-server shows the VBASE2 dataset within the Ensembl Genome Browser and links to the database.
Epitome	Epitome is a database of all known antigenic residues and the antibodies that interact with them, including a detailed description of the residues involved in the interaction and their sequence/structure environments. Each entry in the database describes one interaction between a residue on an antigenic protein and a residue on an antibody chain. Every interaction is described using the following parameters: PDB identifier, antigen chain ID PDB position of the antigenic residue, type of antigenic residue and its sequence environment, antigen residue secondary structure state, antigen residue solvent accessibility, antibody chain ID, type of antibody chain (heavy or light), CDR number, PDB position of the antibody residue, and type of antibody residue and its sequence environment. Additionally, interactions can be visualized using an interface to Jmol.
ImmGen	The Immunological Genome consortium database includes expression profiles for more than 250 mouse immune cell types, and several data browsers to study the dataset.

Online resources for allergy information are also available on http://www.allergen.org. Such data is valuable for investigation of cross-reactivity between known allergens and analysis of potential allergenicity in proteins. The Structural Database of Allergen Proteins (SDAP) stores information of allergenic proteins. The Food Allergy Research and Resource Program (FARRP) Protein Allergen-Online Database contains sequences of known and putative allergens derived from scientific literature and public databases. Allergome emphasizes the annotation of allergens that result in an IgE-mediated disease.

Tools

A variety of computational, mathematical and statistical methods are available and reported. These tools are helpful for collection, analysis, and interpretation of immunological data. They include text mining, information management, sequence analysis, analysis of molecular interactions, and mathematical models that enable advanced simulations of immune system and immunological processes. Attempts are being made for the extraction of interesting and complex patterns from non-structured text documents in the immunological domain. Such as categorization of allergen cross-reactivity information, identification of cancer-associated gene variants and the classification of immune epitopes. 

Immunoinformatics is using the basic bioinformatics tools such as ClustalW, BLAST, and TreeView, as well as specialized immunoinformatics tools, such as EpiMatrix, IMGT/V-QUEST for IG and TR sequence analysis, IMGT/ Collier-de-Perles and IMGT/StructuralQuery for IG variable domain structure analysis. Methods that rely on sequence comparison are diverse and have been applied to analyze HLA sequence conservation, help verify the origins of human immunodeficiency virus (HIV) sequences, and construct homology models for the analysis of hepatitis B virus polymerase resistance to lamivudine and emtricitabine. 

There are also some computational models which focus on protein–protein interactions and networks. There are also tools which are used for T and B cell epitope mapping, proteasomal cleavage site prediction, and TAP– peptide prediction. The experimental data is very much important to design and justify the models to predict various molecular targets. Computational immunology tools is the game between experimental data and mathematically designed computational tools.

Applications

Allergies

Allergies, while a critical subject of immunology, also vary considerably among individuals and sometimes even among genetically similar individuals. The assessment of protein allergenic potential focuses on three main aspects: (i) immunogenicity; (ii) cross-reactivity; and (iii) clinical symptoms. Immunogenicity is due to responses of an IgE antibody-producing B cell and/or of a T cell to a particular allergen. Therefore, immunogenicity studies focus mainly on identifying recognition sites of B-cells and T-cells for allergens. The three-dimensional structural properties of allergens control their allergenicity. 

The use of immunoinformatics tools can be useful to predict protein allergenicity and will become increasingly important in the screening of novel foods before their wide-scale release for human use. Thus, there are major efforts under way to make reliable broad based allergy databases and combine these with well validated prediction tools in order to enable the identification of potential allergens in genetically modified drugs and foods. Though the developments are on primary stage, the World Health organization and Food and Agriculture Organization have proposed guidelines for evaluating allergenicity of genetically modified foods. According to the Codex alimentarius, a protein is potentially allergenic if it possesses an identity of ≥6 contiguous amino acids or ≥ 35% sequence similarity over an 80 amino acid window with a known allergen. Though there are rules, their inherent limitations have started to become apparent and exceptions to the rules have been well reported. 

Infectious diseases and host responses

In the study of infectious diseases and host responses, the mathematical and computer models are a great help. These models were very useful in characterizing the behavior and spread of infectious disease, by understanding the dynamics of the pathogen in the host and the mechanisms of host factors which aid pathogen persistence. Examples include Plasmodium falciparum and nematode infection in ruminants.

Much has been done in understanding immune responses to various pathogens by integrating genomics and proteomics with bioinformatics strategies. Many exciting developments in large-scale screening of pathogens are currently taking place. National Institute of Allergy and Infectious Diseases (NIAID) has initiated an endeavor for systematic mapping of B and T cell epitopes of category A-C pathogens. These pathogens include Bacillus anthracis (anthrax), Clostridium botulinum toxin (botulism), Variola major (smallpox), Francisella tularensis (tularemia), viral hemorrhagic fevers, Burkholderia pseudomallei, Staphylococcus enterotoxin B, yellow fever, influenza, rabies, Chikungunya virus etc. Rule-based systems have been reported for the automated extraction and curation of influenza A records.

This development would lead to the development of an algorithm which would help to identify the conserved regions of pathogen sequences and in turn would be useful for vaccine development. This would be helpful in limiting the spread of infectious disease. Examples include a method for identification of vaccine targets from protein regions of conserved HLA binding and computational assessment of cross-reactivity of broadly neutralizing antibodies against viral pathogens. These examples illustrate the power of immunoinformatics applications to help solve complex problems in public health. Immunoinformatics could accelerate the discovery process dramatically and potentially shorten the time required for vaccine development. Immunoinformatics tools have been used to design the vaccine against Dengue virus  and Leishmania. 

Immune system function

Using this technology it is possible to know the model behind immune system. It has been used to model T-cell-mediated suppression, peripheral lymphocyte migration, T-cell memory, tolerance, thymic function, and antibody networks. Models are helpful to predicts dynamics of pathogen toxicity and T-cell memory in response to different stimuli. There are also several models which are helpful in understanding the nature of specificity in immune network and immunogenicity. 

For example, it was useful to examine the functional relationship between TAP peptide transport and HLA class I antigen presentation. TAP is a transmembrane protein responsible for the transport of antigenic peptides into the endoplasmic reticulum, where MHC them class I molecules can bind them and presented to T cells. As TAP does not bind all peptides equally, TAP-binding affinity could influence the ability of a particular peptide to gain access to the MHC class I pathway. Artificial neural network (ANN), a computer model was used to study peptide binding to human TAP and its relationship with MHC class I binding. The affinity of HLA-binding peptides for TAP was found to differ according to the HLA supertype concerned using this method. This research could have important implications for the design of peptide based immuno-therapeutic drugs and vaccines. It shows the power of the modeling approach to understand complex immune interactions.

There exist also methods which integrate peptide prediction tools with computer simulations that can provide detailed information on the immune response dynamics specific to the given pathogen's peptides.

Cancer Informatics

Cancer is the result of somatic mutations which provide cancer cells with a selective growth advantage. Recently it has been very important to determine the novel mutations. Genomics and proteomics techniques are used worldwide to identify mutations related to each specific cancer and their treatments. Computational tools are used to predict growth and surface antigens on cancerous cells. There are publications explaining a targeted approach for assessing mutations and cancer risk. Algorithm CanPredict was used to indicate how closely a specific gene resembles known cancer-causing genes. Cancer immunology has been given so much importance that the data related to it is growing rapidly. Protein–protein interaction networks provide valuable information on tumorigenesis in humans. Cancer proteins exhibit a network topology that is different from normal proteins in the human interactome. Immunoinformatics have been useful in increasing success of tumour vaccination. Recently, pioneering works have been conducted to analyse the host immune system dynamics in response to artificial immunity induced by vaccination strategies. Other simulation tools use predicted cancer peptides to forecast immune specific anticancer responses that is dependent on the specified HLA. These resources are likely to grow significantly in the near future and immunoinformatics will be a major growth area in this domain.

Immune system

From Wikipedia, the free encyclopedia

A scanning electron microscope image of a single neutrophil (yellow), engulfing anthrax bacteria (orange)

The immune system is a host defense system comprising many biological structures and processes within an organism that protects against disease. To function properly, an immune system must detect a wide variety of agents, known as pathogens, from viruses to parasitic worms, and distinguish them from the organism's own healthy tissue. In many species, the immune system can be classified into subsystems, such as the innate immune system versus the adaptive immune system, or humoral immunity versus cell-mediated immunity. In humans, the blood–brain barrier, blood–cerebrospinal fluid barrier, and similar fluid–brain barriers separate the peripheral immune system from the neuroimmune system, which protects the brain. 

Pathogens can rapidly evolve and adapt, and thereby avoid detection and neutralization by the immune system; however, multiple defense mechanisms have also evolved to recognize and neutralize pathogens. Even simple unicellular organisms such as bacteria possess a rudimentary immune system in the form of enzymes that protect against bacteriophage infections. Other basic immune mechanisms evolved in ancient eukaryotes and remain in their modern descendants, such as plants and invertebrates. These mechanisms include phagocytosis, antimicrobial peptides called defensins, and the complement system. Jawed vertebrates, including humans, have even more sophisticated defense mechanisms, including the ability to adapt over time to recognize specific pathogens more efficiently. Adaptive (or acquired) immunity creates immunological memory after an initial response to a specific pathogen, leading to an enhanced response to subsequent encounters with that same pathogen. This process of acquired immunity is the basis of vaccination. 

Disorders of the immune system can result in autoimmune diseases, inflammatory diseases and cancer. Immunodeficiency occurs when the immune system is less active than normal, resulting in recurring and life-threatening infections. In humans, immunodeficiency can either be the result of a genetic disease such as severe combined immunodeficiency, acquired conditions such as HIV/AIDS, or the use of immunosuppressive medication. In contrast, autoimmunity results from a hyperactive immune system attacking normal tissues as if they were foreign organisms. Common autoimmune diseases include Hashimoto's thyroiditis, rheumatoid arthritis, diabetes mellitus type 1, and systemic lupus erythematosus. Immunology covers the study of all aspects of the immune system.

History of immunology

Immunology is a science that examines the structure and function of the immune system. It originates from medicine and early studies on the causes of immunity to disease. The earliest known reference to immunity was during the plague of Athens in 430 BC. Thucydides noted that people who had recovered from a previous bout of the disease could nurse the sick without contracting the illness a second time. In the 18th century, Pierre-Louis Moreau de Maupertuis made experiments with scorpion venom and observed that certain dogs and mice were immune to this venom. This and other observations of acquired immunity were later exploited by Louis Pasteur in his development of vaccination and his proposed germ theory of disease. Pasteur's theory was in direct opposition to contemporary theories of disease, such as the miasma theory. It was not until Robert Koch's 1891 proofs, for which he was awarded a Nobel Prize in 1905, that microorganisms were confirmed as the cause of infectious disease. Viruses were confirmed as human pathogens in 1901, with the discovery of the yellow fever virus by Walter Reed.

Immunology made a great advance towards the end of the 19th century, through rapid developments, in the study of humoral immunity and cellular immunity. Particularly important was the work of Paul Ehrlich, who proposed the side-chain theory to explain the specificity of the antigen-antibody reaction; his contributions to the understanding of humoral immunity were recognized by the award of a Nobel Prize in 1908, which was jointly awarded to the founder of cellular immunology, Elie Metchnikoff.

Layered defense

The immune system protects organisms from infection with layered defenses of increasing specificity. In simple terms, physical barriers prevent pathogens such as bacteria and viruses from entering the organism. If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems are found in all plants and animals. If pathogens successfully evade the innate response, vertebrates possess a second layer of protection, the adaptive immune system, which is activated by the innate response. Here, the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered.

Components of the immune system

Innate immune system	Adaptive immune system
Response is non-specific	Pathogen and antigen specific response
Exposure leads to immediate maximal response	Lag time between exposure and maximal response
Cell-mediated and humoral components	Cell-mediated and humoral components
No immunological memory	Exposure leads to immunological memory
Found in nearly all forms of life	Found only in jawed vertebrates

Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non-self molecules. In immunology, self molecules are those components of an organism's body that can be distinguished from foreign substances by the immune system. Conversely, non-self molecules are those recognized as foreign molecules. One class of non-self molecules are called antigens (short for antibody generators) and are defined as substances that bind to specific immune receptors and elicit an immune response.

Innate immune system

Microorganisms or toxins that successfully enter an organism encounter the cells and mechanisms of the innate immune system. The innate response is usually triggered when microbes are identified by pattern recognition receptors, which recognize components that are conserved among broad groups of microorganisms, or when damaged, injured or stressed cells send out alarm signals, many of which (but not all) are recognized by the same receptors as those that recognize pathogens. Innate immune defenses are non-specific, meaning these systems respond to pathogens in a generic way. This system does not confer long-lasting immunity against a pathogen. The innate immune system is the dominant system of host defense in most organisms.

Surface barriers

Several barriers protect organisms from infection, including mechanical, chemical, and biological barriers. The waxy cuticle of most leaves, the exoskeleton of insects, the shells and membranes of externally deposited eggs, and skin are examples of mechanical barriers that are the first line of defense against infection. However, as organisms cannot be completely sealed from their environments, other systems act to protect body openings such as the lungs, intestines, and the genitourinary tract. In the lungs, coughing and sneezing mechanically eject pathogens and other irritants from the respiratory tract. The flushing action of tears and urine also mechanically expels pathogens, while mucus secreted by the respiratory and gastrointestinal tract serves to trap and entangle microorganisms.

Chemical barriers also protect against infection. The skin and respiratory tract secrete antimicrobial peptides such as the β-defensins. Enzymes such as lysozyme and phospholipase A2 in saliva, tears, and breast milk are also antibacterials. Vaginal secretions serve as a chemical barrier following menarche, when they become slightly acidic, while semen contains defensins and zinc to kill pathogens. In the stomach, gastric acid and proteases serve as powerful chemical defenses against ingested pathogens. 

Within the genitourinary and gastrointestinal tracts, commensal flora serve as biological barriers by competing with pathogenic bacteria for food and space and, in some cases, by changing the conditions in their environment, such as pH or available iron. As a result of the symbiotic relationship between commensals and the immune system, the probability that pathogens will reach sufficient numbers to cause illness is reduced. However, since most antibiotics non-specifically target bacteria and do not affect fungi, oral antibiotics can lead to an "overgrowth" of fungi and cause conditions such as a vaginal candidiasis (a yeast infection). There is good evidence that re-introduction of probiotic flora, such as pure cultures of the lactobacilli normally found in unpasteurized yogurt, helps restore a healthy balance of microbial populations in intestinal infections in children and encouraging preliminary data in studies on bacterial gastroenteritis, inflammatory bowel diseases, urinary tract infection and post-surgical infections.

Inflammation

Inflammation is one of the first responses of the immune system to infection. The symptoms of inflammation are redness, swelling, heat, and pain, which are caused by increased blood flow into tissue. Inflammation is produced by eicosanoids and cytokines, which are released by injured or infected cells. Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain white blood cells (leukocytes). Common cytokines include interleukins that are responsible for communication between white blood cells; chemokines that promote chemotaxis; and interferons that have anti-viral effects, such as shutting down protein synthesis in the host cell. Growth factors and cytotoxic factors may also be released. These cytokines and other chemicals recruit immune cells to the site of infection and promote healing of any damaged tissue following the removal of pathogens.

Complement system

The complement system is a biochemical cascade that attacks the surfaces of foreign cells. It contains over 20 different proteins and is named for its ability to "complement" the killing of pathogens by antibodies. Complement is the major humoral component of the innate immune response. Many species have complement systems, including non-mammals like plants, fish, and some invertebrates.

In humans, this response is activated by complement binding to antibodies that have attached to these microbes or the binding of complement proteins to carbohydrates on the surfaces of microbes. This recognition signal triggers a rapid killing response. The speed of the response is a result of signal amplification that occurs after sequential proteolytic activation of complement molecules, which are also proteases. After complement proteins initially bind to the microbe, they activate their protease activity, which in turn activates other complement proteases, and so on. This produces a catalytic cascade that amplifies the initial signal by controlled positive feedback. The cascade results in the production of peptides that attract immune cells, increase vascular permeability, and opsonize (coat) the surface of a pathogen, marking it for destruction. This deposition of complement can also kill cells directly by disrupting their plasma membrane.

Cellular barriers

A scanning electron microscope image of normal circulating human blood. One can see red blood cells, several knobby white blood cells including lymphocytes, a monocyte, a neutrophil, and many small disc-shaped platelets.

Leukocytes (white blood cells) act like independent, single-celled organisms and are the second arm of the innate immune system. The innate leukocytes include the phagocytes (macrophages, neutrophils, and dendritic cells), innate lymphoid cells, mast cells, eosinophils, basophils, and natural killer cells. These cells identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms. Innate cells are also important mediators in lymphoid organ development and the activation of the adaptive immune system.

Phagocytosis is an important feature of cellular innate immunity performed by cells called phagocytes that engulf, or eat, pathogens or particles. Phagocytes generally patrol the body searching for pathogens, but can be called to specific locations by cytokines. Once a pathogen has been engulfed by a phagocyte, it becomes trapped in an intracellular vesicle called a phagosome, which subsequently fuses with another vesicle called a lysosome to form a phagolysosome. The pathogen is killed by the activity of digestive enzymes or following a respiratory burst that releases free radicals into the phagolysosome. Phagocytosis evolved as a means of acquiring nutrients, but this role was extended in phagocytes to include engulfment of pathogens as a defense mechanism. Phagocytosis probably represents the oldest form of host defense, as phagocytes have been identified in both vertebrate and invertebrate animals.

Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens. Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, normally representing 50% to 60% of the total circulating leukocytes, and consisting of neutrophil-killer and neutrophil-cager subpopulations. During the acute phase of inflammation, particularly as a result of bacterial infection, neutrophils migrate toward the site of inflammation in a process called chemotaxis, and are usually the first cells to arrive at the scene of infection. Macrophages are versatile cells that reside within tissues and produce a wide array of chemicals including enzymes, complement proteins, and cytokines, while they can also act as scavengers that rid the body of worn-out cells and other debris, and as antigen-presenting cells that activate the adaptive immune system.

Dendritic cells (DC) are phagocytes in tissues that are in contact with the external environment; therefore, they are located mainly in the skin, nose, lungs, stomach, and intestines. They are named for their resemblance to neuronal dendrites, as both have many spine-like projections, but dendritic cells are in no way connected to the nervous system. Dendritic cells serve as a link between the bodily tissues and the innate and adaptive immune systems, as they present antigens to T cells, one of the key cell types of the adaptive immune system.

Mast cells reside in connective tissues and mucous membranes, and regulate the inflammatory response. They are most often associated with allergy and anaphylaxis. Basophils and eosinophils are related to neutrophils. They secrete chemical mediators that are involved in defending against parasites and play a role in allergic reactions, such as asthma. Natural killer (NK cells) cells are leukocytes that attack and destroy tumor cells, or cells that have been infected by viruses.

Natural killer cells

Natural killer cells, or NK cells, are lymphocytes and a component of the innate immune system which does not directly attack invading microbes. Rather, NK cells destroy compromised host cells, such as tumor cells or virus-infected cells, recognizing such cells by a condition known as "missing self." This term describes cells with low levels of a cell-surface marker called MHC I (major histocompatibility complex) – a situation that can arise in viral infections of host cells. They were named "natural killer" because of the initial notion that they do not require activation in order to kill cells that are "missing self." For many years it was unclear how NK cells recognize tumor cells and infected cells. It is now known that the MHC makeup on the surface of those cells is altered and the NK cells become activated through recognition of "missing self". Normal body cells are not recognized and attacked by NK cells because they express intact self MHC antigens. Those MHC antigens are recognized by killer cell immunoglobulin receptors (KIR) which essentially put the brakes on NK cells.

Adaptive immune system

The adaptive immune system evolved in early vertebrates and allows for a stronger immune response as well as immunological memory, where each pathogen is "remembered" by a signature antigen. The adaptive immune response is antigen-specific and requires the recognition of specific "non-self" antigens during a process called antigen presentation. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by "memory cells". Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it.

Lymphocytes

The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response. 

Both B cells and T cells carry receptor molecules that recognize specific targets. T cells recognize a "non-self" target, such as a pathogen, only after antigens (small fragments of the pathogen) have been processed and presented in combination with a "self" receptor called a major histocompatibility complex (MHC) molecule. There are two major subtypes of T cells: the killer T cell and the helper T cell. In addition there are regulatory T cells which have a role in modulating immune response. Killer T cells only recognize antigens coupled to Class I MHC molecules, while helper T cells and regulatory T cells only recognize antigens coupled to Class II MHC molecules. These two mechanisms of antigen presentation reflect the different roles of the two types of T cell. A third, minor subtype are the γδ T cells that recognize intact antigens that are not bound to MHC receptors. The double-positive T cells are exposed to a wide variety of self-antigens in the thymus, in which iodine is necessary for its thymus development and activity.

In contrast, the B cell antigen-specific receptor is an antibody molecule on the B cell surface, and recognizes whole pathogens without any need for antigen processing. Each lineage of B cell expresses a different antibody, so the complete set of B cell antigen receptors represent all the antibodies that the body can manufacture.

Killer T cells

Killer T cells are a sub-group of T cells that kill cells that are infected with viruses (and other pathogens), or are otherwise damaged or dysfunctional. As with B cells, each type of T cell recognizes a different antigen. Killer T cells are activated when their T-cell receptor (TCR) binds to this specific antigen in a complex with the MHC Class I receptor of another cell. Recognition of this MHC:antigen complex is aided by a co-receptor on the T cell, called CD8. The T cell then travels throughout the body in search of cells where the MHC I receptors bear this antigen. When an activated T cell contacts such cells, it releases cytotoxins, such as perforin, which form pores in the target cell's plasma membrane, allowing ions, water and toxins to enter. The entry of another toxin called granulysin (a protease) induces the target cell to undergo apoptosis. T cell killing of host cells is particularly important in preventing the replication of viruses. T cell activation is tightly controlled and generally requires a very strong MHC/antigen activation signal, or additional activation signals provided by "helper" T cells (see below).

Helper T cells

Function of T helper cells: Antigen-presenting cells (APCs) present antigen on their Class II MHC molecules (MHC2). Helper T cells recognize these, with the help of their expression of CD4 co-receptor (CD4+). The activation of a resting helper T cell causes it to release cytokines and other stimulatory signals (green arrows) that stimulate the activity of macrophages, killer T cells and B cells, the latter producing antibodies. The stimulation of B cells and macrophages succeeds a proliferation of T helper cells.

Helper T cells regulate both the innate and adaptive immune responses and help determine which immune responses the body makes to a particular pathogen. These cells have no cytotoxic activity and do not kill infected cells or clear pathogens directly. They instead control the immune response by directing other cells to perform these tasks. 

Helper T cells express T cell receptors (TCR) that recognize antigen bound to Class II MHC molecules. The MHC:antigen complex is also recognized by the helper cell's CD4 co-receptor, which recruits molecules inside the T cell (e.g., Lck) that are responsible for the T cell's activation. Helper T cells have a weaker association with the MHC:antigen complex than observed for killer T cells, meaning many receptors (around 200–300) on the helper T cell must be bound by an MHC:antigen in order to activate the helper cell, while killer T cells can be activated by engagement of a single MHC:antigen molecule. Helper T cell activation also requires longer duration of engagement with an antigen-presenting cell. The activation of a resting helper T cell causes it to release cytokines that influence the activity of many cell types. Cytokine signals produced by helper T cells enhance the microbicidal function of macrophages and the activity of killer T cells. In addition, helper T cell activation causes an upregulation of molecules expressed on the T cell's surface, such as CD40 ligand (also called CD154), which provide extra stimulatory signals typically required to activate antibody-producing B cells.

Gamma delta T cells

Gamma delta T cells (γδ T cells) possess an alternative T-cell receptor (TCR) as opposed to CD4+ and CD8+ (αβ) T cells and share the characteristics of helper T cells, cytotoxic T cells and NK cells. The conditions that produce responses from γδ T cells are not fully understood. Like other 'unconventional' T cell subsets bearing invariant TCRs, such as CD1d-restricted Natural Killer T cells, γδ T cells straddle the border between innate and adaptive immunity. On one hand, γδ T cells are a component of adaptive immunity as they rearrange TCR genes to produce receptor diversity and can also develop a memory phenotype. On the other hand, the various subsets are also part of the innate immune system, as restricted TCR or NK receptors may be used as pattern recognition receptors. For example, large numbers of human Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted Vδ1+ T cells in epithelia respond to stressed epithelial cells.

An antibody is made up of two heavy chains and two light chains. The unique variable region allows an antibody to recognize its matching antigen.

B lymphocytes and antibodies

A B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen. This antigen/antibody complex is taken up by the B cell and processed by proteolysis into peptides. The B cell then displays these antigenic peptides on its surface MHC class II molecules. This combination of MHC and antigen attracts a matching helper T cell, which releases lymphokines and activates the B cell. As the activated B cell then begins to divide, its offspring (plasma cells) secrete millions of copies of the antibody that recognizes this antigen. These antibodies circulate in blood plasma and lymph, bind to pathogens expressing the antigen and mark them for destruction by complement activation or for uptake and destruction by phagocytes. Antibodies can also neutralize challenges directly, by binding to bacterial toxins or by interfering with the receptors that viruses and bacteria use to infect cells.

Alternative adaptive immune system

Evolution of the adaptive immune system occurred in an ancestor of the jawed vertebrates. Many of the classical molecules of the adaptive immune system (e.g., immunoglobulins and T-cell receptors) exist only in jawed vertebrates. However, a distinct lymphocyte-derived molecule has been discovered in primitive jawless vertebrates, such as the lamprey and hagfish. These animals possess a large array of molecules called Variable lymphocyte receptors (VLRs) that, like the antigen receptors of jawed vertebrates, are produced from only a small number (one or two) of genes. These molecules are believed to bind pathogenic antigens in a similar way to antibodies, and with the same degree of specificity.

Immunological memory

When B cells and T cells are activated and begin to replicate, some of their offspring become long-lived memory cells. Throughout the lifetime of an animal, these memory cells remember each specific pathogen encountered and can mount a strong response if the pathogen is detected again. This is "adaptive" because it occurs during the lifetime of an individual as an adaptation to infection with that pathogen and prepares the immune system for future challenges. Immunological memory can be in the form of either passive short-term memory or active long-term memory.

Passive memory

Newborn infants have no prior exposure to microbes and are particularly vulnerable to infection. Several layers of passive protection are provided by the mother. During pregnancy, a particular type of antibody, called IgG, is transported from mother to baby directly through the placenta, so human babies have high levels of antibodies even at birth, with the same range of antigen specificities as their mother. Breast milk or colostrum also contains antibodies that are transferred to the gut of the infant and protect against bacterial infections until the newborn can synthesize its own antibodies. This is passive immunity because the fetus does not actually make any memory cells or antibodies—it only borrows them. This passive immunity is usually short-term, lasting from a few days up to several months. In medicine, protective passive immunity can also be transferred artificially from one individual to another via antibody-rich serum.

The time-course of an immune response begins with the initial pathogen encounter, (or initial vaccination) and leads to the formation and maintenance of active immunological memory.

Active memory and immunization

Long-term active memory is acquired following infection by activation of B and T cells. Active immunity can also be generated artificially, through vaccination. The principle behind vaccination (also called immunization) is to introduce an antigen from a pathogen in order to stimulate the immune system and develop specific immunity against that particular pathogen without causing disease associated with that organism. This deliberate induction of an immune response is successful because it exploits the natural specificity of the immune system, as well as its inducibility. With infectious disease remaining one of the leading causes of death in the human population, vaccination represents the most effective manipulation of the immune system mankind has developed.

Most viral vaccines are based on live attenuated viruses, while many bacterial vaccines are based on acellular components of micro-organisms, including harmless toxin components. Since many antigens derived from acellular vaccines do not strongly induce the adaptive response, most bacterial vaccines are provided with additional adjuvants that activate the antigen-presenting cells of the innate immune system and maximize immunogenicity.

Disorders of human immunity

The immune system is a remarkably effective structure that incorporates specificity, inducibility and adaptation. Failures of host defense do occur, however, and fall into three broad categories: immunodeficiencies, autoimmunity, and hypersensitivities.

Immunodeficiencies

Immunodeficiencies occur when one or more of the components of the immune system are inactive. The ability of the immune system to respond to pathogens is diminished in both the young and the elderly, with immune responses beginning to decline at around 50 years of age due to immunosenescence. In developed countries, obesity, alcoholism, and drug use are common causes of poor immune function. However, malnutrition is the most common cause of immunodeficiency in developing countries. Diets lacking sufficient protein are associated with impaired cell-mediated immunity, complement activity, phagocyte function, IgA antibody concentrations, and cytokine production. Additionally, the loss of the thymus at an early age through genetic mutation or surgical removal results in severe immunodeficiency and a high susceptibility to infection.

Immunodeficiencies can also be inherited or 'acquired'. Chronic granulomatous disease, where phagocytes have a reduced ability to destroy pathogens, is an example of an inherited, or congenital, immunodeficiency. AIDS and some types of cancer cause acquired immunodeficiency.

Autoimmunity

Overactive immune responses comprise the other end of immune dysfunction, particularly the autoimmune disorders. Here, the immune system fails to properly distinguish between self and non-self, and attacks part of the body. Under normal circumstances, many T cells and antibodies react with "self" peptides. One of the functions of specialized cells (located in the thymus and bone marrow) is to present young lymphocytes with self antigens produced throughout the body and to eliminate those cells that recognize self-antigens, preventing autoimmunity.

Hypersensitivity

Hypersensitivity is an immune response that damages the body's own tissues. They are divided into four classes (Type I – IV) based on the mechanisms involved and the time course of the hypersensitive reaction. Type I hypersensitivity is an immediate or anaphylactic reaction, often associated with allergy. Symptoms can range from mild discomfort to death. Type I hypersensitivity is mediated by IgE, which triggers degranulation of mast cells and basophils when cross-linked by antigen. Type II hypersensitivity occurs when antibodies bind to antigens on the patient's own cells, marking them for destruction. This is also called antibody-dependent (or cytotoxic) hypersensitivity, and is mediated by IgG and IgM antibodies. Immune complexes (aggregations of antigens, complement proteins, and IgG and IgM antibodies) deposited in various tissues trigger Type III hypersensitivity reactions. Type IV hypersensitivity (also known as cell-mediated or delayed type hypersensitivity) usually takes between two and three days to develop. Type IV reactions are involved in many autoimmune and infectious diseases, but may also involve contact dermatitis (poison ivy). These reactions are mediated by T cells, monocytes, and macrophages.

Idiopatic inflammation

Inflammation is one of the first responses of the immune system to infection, but it can appear without known cause. 

Inflammation is produced by eicosanoids and cytokines, which are released by injured or infected cells. Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain white blood cells (leukocytes). Common cytokines include interleukins that are responsible for communication between white blood cells; chemokines that promote chemotaxis; and interferons that have anti-viral effects, such as shutting down protein synthesis in the host cell. Growth factors and cytotoxic factors may also be released. These cytokines and other chemicals recruit immune cells to the site of infection and promote healing of any damaged tissue following the removal of pathogens.

Other mechanisms and evolution

It is likely that a multicomponent, adaptive immune system arose with the first vertebrates, as invertebrates do not generate lymphocytes or an antibody-based humoral response. Many species, however, utilize mechanisms that appear to be precursors of these aspects of vertebrate immunity. Immune systems appear even in the structurally most simple forms of life, with bacteria using a unique defense mechanism, called the restriction modification system to protect themselves from viral pathogens, called bacteriophages. Prokaryotes also possess acquired immunity, through a system that uses CRISPR sequences to retain fragments of the genomes of phage that they have come into contact with in the past, which allows them to block virus replication through a form of RNA interference. Prokaryotes also possess other defense mechanisms. Offensive elements of the immune systems are also present in unicellular eukaryotes, but studies of their roles in defense are few.

Pattern recognition receptors are proteins used by nearly all organisms to identify molecules associated with pathogens. Antimicrobial peptides called defensins are an evolutionarily conserved component of the innate immune response found in all animals and plants, and represent the main form of invertebrate systemic immunity. The complement system and phagocytic cells are also used by most forms of invertebrate life. Ribonucleases and the RNA interference pathway are conserved across all eukaryotes, and are thought to play a role in the immune response to viruses.

Unlike animals, plants lack phagocytic cells, but many plant immune responses involve systemic chemical signals that are sent through a plant. Individual plant cells respond to molecules associated with pathogens known as Pathogen-associated molecular patterns or PAMPs. When a part of a plant becomes infected, the plant produces a localized hypersensitive response, whereby cells at the site of infection undergo rapid apoptosis to prevent the spread of the disease to other parts of the plant. Systemic acquired resistance (SAR) is a type of defensive response used by plants that renders the entire plant resistant to a particular infectious agent. RNA silencing mechanisms are particularly important in this systemic response as they can block virus replication.

Tumor immunology

Macrophages have identified a cancer cell (the large, spiky mass). Upon fusing with the cancer cell, the macrophages (smaller white cells) inject toxins that kill the tumor cell. Immunotherapy for the treatment of cancer is an active area of medical research.

 

Another important role of the immune system is to identify and eliminate tumors. This is called immune surveillance. The transformed cells of tumors express antigens that are not found on normal cells. To the immune system, these antigens appear foreign, and their presence causes immune cells to attack the transformed tumor cells. The antigens expressed by tumors have several sources; some are derived from oncogenic viruses like human papillomavirus, which causes cervical cancer, while others are the organism's own proteins that occur at low levels in normal cells but reach high levels in tumor cells. One example is an enzyme called tyrosinase that, when expressed at high levels, transforms certain skin cells (e.g. melanocytes) into tumors called melanomas. A third possible source of tumor antigens are proteins normally important for regulating cell growth and survival, that commonly mutate into cancer inducing molecules called oncogenes.

The main response of the immune system to tumors is to destroy the abnormal cells using killer T cells, sometimes with the assistance of helper T cells. Tumor antigens are presented on MHC class I molecules in a similar way to viral antigens. This allows killer T cells to recognize the tumor cell as abnormal. NK cells also kill tumorous cells in a similar way, especially if the tumor cells have fewer MHC class I molecules on their surface than normal; this is a common phenomenon with tumors. Sometimes antibodies are generated against tumor cells allowing for their destruction by the complement system.

Clearly, some tumors evade the immune system and go on to become cancers. Tumor cells often have a reduced number of MHC class I molecules on their surface, thus avoiding detection by killer T cells. Some tumor cells also release products that inhibit the immune response; for example by secreting the cytokine TGF-β, which suppresses the activity of macrophages and lymphocytes. In addition, immunological tolerance may develop against tumor antigens, so the immune system no longer attacks the tumor cells.

Paradoxically, macrophages can promote tumor growth  when tumor cells send out cytokines that attract macrophages, which then generate cytokines and growth factors such as tumor-necrosis factor alpha that nurture tumor development or promote stem-cell-like plasticity. In addition, a combination of hypoxia in the tumor and a cytokine produced by macrophages induces tumor cells to decrease production of a protein that blocks metastasis and thereby assists spread of cancer cells.

Physiological regulation

The immune system is involved in many aspects of physiological regulation in the body. The immune system interacts intimately with other systems, such as the endocrine and the nervous systems. The immune system also plays a crucial role in embryogenesis (development of the embryo), as well as in tissue repair and regeneration.

Hormones

Hormones can act as immunomodulators, altering the sensitivity of the immune system. For example, female sex hormones are known immunostimulators of both adaptive and innate immune responses. Some autoimmune diseases such as lupus erythematosus strike women preferentially, and their onset often coincides with puberty. By contrast, male sex hormones such as testosterone seem to be immunosuppressive. Other hormones appear to regulate the immune system as well, most notably prolactin, growth hormone and vitamin D.

Vitamin D

When a T-cell encounters a foreign pathogen, it extends a vitamin D receptor. This is essentially a signaling device that allows the T-cell to bind to the active form of vitamin D, the steroid hormone calcitriol. T-cells have a symbiotic relationship with vitamin D. Not only does the T-cell extend a vitamin D receptor, in essence asking to bind to the steroid hormone version of vitamin D, calcitriol, but the T-cell expresses the gene CYP27B1, which is the gene responsible for converting the pre-hormone version of vitamin D, calcidiol into the steroid hormone version, calcitriol. Only after binding to calcitriol can T-cells perform their intended function. Other immune system cells that are known to express CYP27B1 and thus activate vitamin D calcidiol, are dendritic cells, keratinocytes and macrophages.

It is conjectured that a progressive decline in hormone levels with age is partially responsible for weakened immune responses in aging individuals. Conversely, some hormones are regulated by the immune system, notably thyroid hormone activity. The age-related decline in immune function is also related to decreasing vitamin D levels in the elderly. As people age, two things happen that negatively affect their vitamin D levels. First, they stay indoors more due to decreased activity levels. This means that they get less sun and therefore produce less cholecalciferol via UVB radiation. Second, as a person ages the skin becomes less adept at producing vitamin D.

Sleep and rest

The immune system is affected by sleep and rest, and sleep deprivation is detrimental to immune function. Complex feedback loops involving cytokines, such as interleukin-1 and tumor necrosis factor-α produced in response to infection, appear to also play a role in the regulation of non-rapid eye movement (REM) sleep. Thus the immune response to infection may result in changes to the sleep cycle, including an increase in slow-wave sleep relative to REM sleep.

When suffering from sleep deprivation, active immunizations may have a diminished effect and may result in lower antibody production, and a lower immune response, than would be noted in a well-rested individual. Additionally, proteins such as NFIL3, which have been shown to be closely intertwined with both T-cell differentiation and our circadian rhythms, can be affected through the disturbance of natural light and dark cycles through instances of sleep deprivation, shift work, etc. As a result, these disruptions can lead to an increase in chronic conditions such as heart disease, chronic pain, and asthma.

In addition to the negative consequences of sleep deprivation, sleep and the intertwined circadian system have been shown to have strong regulatory effects on immunological functions affecting both the innate and the adaptive immunity. First, during the early slow-wave-sleep stage, a sudden drop in blood levels of cortisol, epinephrine, and norepinephrine induce increased blood levels of the hormones leptin, pituitary growth hormone, and prolactin. These signals induce a pro-inflammatory state through the production of the pro-inflammatory cytokines interleukin-1, interleukin-12, TNF-alpha and IFN-gamma. These cytokines then stimulate immune functions such as immune cells activation, proliferation, and differentiation. It is during this time that undifferentiated, or less differentiated, like naïve and central memory T cells, peak (i.e. during a time of a slowly evolving adaptive immune response). In addition to these effects, the milieu of hormones produced at this time (leptin, pituitary growth hormone, and prolactin) support the interactions between APCs and T-cells, a shift of the T_h1/T_h2 cytokine balance towards one that supports T_h1, an increase in overall T_h cell proliferation, and naïve T cell migration to lymph nodes. This milieu is also thought to support the formation of long-lasting immune memory through the initiation of Th1 immune responses.

In contrast, during wake periods differentiated effector cells, such as cytotoxic natural killer cells and CTLs (cytotoxic T lymphocytes), peak in order to elicit an effective response against any intruding pathogens. As well during awake active times, anti-inflammatory molecules, such as cortisol and catecholamines, peak. There are two theories as to why the pro-inflammatory state is reserved for sleep time. First, inflammation would cause serious cognitive and physical impairments if it were to occur during wake times. Second, inflammation may occur during sleep times due to the presence of melatonin. Inflammation causes a great deal of oxidative stress and the presence of melatonin during sleep times could actively counteract free radical production during this time.

Nutrition and diet

Overnutrition is associated with diseases such as diabetes and obesity, which are known to affect immune function. More moderate malnutrition, as well as certain specific trace mineral and nutrient deficiencies, can also compromise the immune response.

Foods rich in certain fatty acids may foster a healthy immune system. Likewise, fetal undernourishment can cause a lifelong impairment of the immune system.

Repair and regeneration

The immune system, particularly the innate component, plays a decisive role in tissue repair after an insult. Key actors include macrophages and neutrophils, but other cellular actors, including γδ T cells, innate lymphoid cells (ILCs), and regulatory T cells (Tregs), are also important. The plasticity of immune cells and the balance between pro-inflammatory and anti-inflammatory signals are crucial aspects of efficient tissue repair. Immune components and pathways are involved in regeneration as well, for example in amphibians. According to one hypothesis, organisms that can regenerate could be less immunocompetent than organisms that cannot regenerate.

Manipulation in medicine

The immunosuppressive drug dexamethasone

The immune response can be manipulated to suppress unwanted responses resulting from autoimmunity, allergy, and transplant rejection, and to stimulate protective responses against pathogens that largely elude the immune system (see immunization) or cancer.

Immunosuppression

Immunosuppressive drugs are used to control autoimmune disorders or inflammation when excessive tissue damage occurs, and to prevent transplant rejection after an organ transplant.

Anti-inflammatory drugs are often used to control the effects of inflammation. Glucocorticoids are the most powerful of these drugs; however, these drugs can have many undesirable side effects, such as central obesity, hyperglycemia, osteoporosis, and their use must be tightly controlled. Lower doses of anti-inflammatory drugs are often used in conjunction with cytotoxic or immunosuppressive drugs such as methotrexate or azathioprine. Cytotoxic drugs inhibit the immune response by killing dividing cells such as activated T cells. However, the killing is indiscriminate and other constantly dividing cells and their organs are affected, which causes toxic side effects. Immunosuppressive drugs such as cyclosporin prevent T cells from responding to signals correctly by inhibiting signal transduction pathways.

Immunostimulation

Cancer immunotherapy covers the medical ways to stimulate the immune system to attack cancer tumours.

Theoretical approaches to the immune system

Immunology is strongly experimental in everyday practice but is also characterized by an ongoing theoretical attitude. Many theories have been suggested in immunology from the end of the nineteenth century up to the present time. The end of the 19th century and the beginning of the 20th century saw a battle between "cellular" and "humoral" theories of immunity. According to the cellular theory of immunity, represented in particular by Elie Metchnikoff, it was cells – more precisely, phagocytes – that were responsible for immune responses. In contrast, the humoral theory of immunity, held, among others, by Robert Koch and Emil von Behring, stated that the active immune agents were soluble components (molecules) found in the organism’s “humors” rather than its cells.

In the mid-1950s, Frank Burnet, inspired by a suggestion made by Niels Jerne, formulated the clonal selection theory (CST) of immunity. On the basis of CST, Burnet developed a theory of how an immune response is triggered according to the self/nonself distinction: "self" constituents (constituents of the body) do not trigger destructive immune responses, while "nonself" entities (pathogens, an allograft) trigger a destructive immune response. The theory was later modified to reflect new discoveries regarding histocompatibility or the complex "two-signal" activation of T cells. The self/nonself theory of immunity and the self/nonself vocabulary have been criticized, but remain very influential.

More recently, several theoretical frameworks have been suggested in immunology, including "autopoietic" views, "cognitive immune" views, the "danger model" (or "danger theory"), and the "discontinuity" theory. The danger model, suggested by Polly Matzinger and colleagues, has been very influential, arousing many comments and discussions.

Predicting immunogenicity

Larger drugs (>500 Da) can provoke a neutralizing immune response, particularly if the drugs are administered repeatedly, or in larger doses. This limits the effectiveness of drugs based on larger peptides and proteins (which are typically larger than 6000 Da). In some cases, the drug itself is not immunogenic, but may be co-administered with an immunogenic compound, as is sometimes the case for Taxol. Computational methods have been developed to predict the immunogenicity of peptides and proteins, which are particularly useful in designing therapeutic antibodies, assessing likely virulence of mutations in viral coat particles, and validation of proposed peptide-based drug treatments. Early techniques relied mainly on the observation that hydrophilic amino acids are overrepresented in epitope regions than hydrophobic amino acids; however, more recent developments rely on machine learning techniques using databases of existing known epitopes, usually on well-studied virus proteins, as a training set. A publicly accessible database has been established for the cataloguing of epitopes from pathogens known to be recognizable by B cells. The emerging field of bioinformatics-based studies of immunogenicity is referred to as immunoinformatics. Immunoproteomics is the study of large sets of proteins (proteomics) involved in the immune response.

Manipulation by pathogens

The success of any pathogen depends on its ability to elude host immune responses. Therefore, pathogens evolved several methods that allow them to successfully infect a host, while evading detection or destruction by the immune system. Bacteria often overcome physical barriers by secreting enzymes that digest the barrier, for example, by using a type II secretion system. Alternatively, using a type III secretion system, they may insert a hollow tube into the host cell, providing a direct route for proteins to move from the pathogen to the host. These proteins are often used to shut down host defenses.

An evasion strategy used by several pathogens to avoid the innate immune system is to hide within the cells of their host (also called intracellular pathogenesis). Here, a pathogen spends most of its life-cycle inside host cells, where it is shielded from direct contact with immune cells, antibodies and complement. Some examples of intracellular pathogens include viruses, the food poisoning bacterium Salmonella and the eukaryotic parasites that cause malaria (Plasmodium falciparum) and leishmaniasis (Leishmania spp.). Other bacteria, such as Mycobacterium tuberculosis, live inside a protective capsule that prevents lysis by complement. Many pathogens secrete compounds that diminish or misdirect the host's immune response. Some bacteria form biofilms to protect themselves from the cells and proteins of the immune system. Such biofilms are present in many successful infections, e.g., the chronic Pseudomonas aeruginosa and Burkholderia cenocepacia infections characteristic of cystic fibrosis. Other bacteria generate surface proteins that bind to antibodies, rendering them ineffective; examples include Streptococcus (protein G), Staphylococcus aureus (protein A), and Peptostreptococcus magnus (protein L).

The mechanisms used to evade the adaptive immune system are more complicated. The simplest approach is to rapidly change non-essential epitopes (amino acids and/or sugars) on the surface of the pathogen, while keeping essential epitopes concealed. This is called antigenic variation. An example is HIV, which mutates rapidly, so the proteins on its viral envelope that are essential for entry into its host target cell are constantly changing. These frequent changes in antigens may explain the failures of vaccines directed at this virus. The parasite Trypanosoma brucei uses a similar strategy, constantly switching one type of surface protein for another, allowing it to stay one step ahead of the antibody response. Masking antigens with host molecules is another common strategy for avoiding detection by the immune system. In HIV, the envelope that covers the virion is formed from the outermost membrane of the host cell; such "self-cloaked" viruses make it difficult for the immune system to identify them as "non-self" structures.