Herpes simplex virus

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Herpes_simplex_virus 

 

Herpes simplex viruses81i2
TEM micrograph of virions of a herpes simplex virus species
Scientific classification
(unranked):	Virus
Realm:	Duplodnaviria
Kingdom:	Heunggongvirae
Phylum:	Peploviricota
Class:	Herviviricetes
Order:	Herpesvirales
Family:	Herpesviridae
Subfamily:	Alphaherpesvirinae
Genus:	Simplexvirus
Groups included
Human alphaherpesvirus 1 Human alphaherpesvirus 2
Cladistically included but traditionally excluded taxa
All other Simplexvirus spp.: Ateline alphaherpesvirus 1 Bovine alphaherpesvirus 2 Cercopithecine alphaherpesvirus 2 Leporid alphaherpesvirus 4 Macacine alphaherpesvirus 1 Macropodid alphaherpesvirus 1 Macropodid alphaherpesvirus 2 Panine alphaherpesvirus 3 Papiine alphaherpesvirus 2 Pteropodid alphaherpesvirus 1 Saimiriine alphaherpesrus 1

Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names Human alphaherpesvirus 1 and Human alphaherpesvirus 2, are two members of the human Herpesviridae family, a set of new viruses that produce viral infections in the majority of humans. Both HSV-1 (which produces most cold sores) and HSV-2 (which produces most genital herpes) are common and contagious. They can be spread when an infected person begins shedding the virus.

About 67% of the world population under the age of 50 has HSV-1. In the United States, about 47.8% and 11.9% are believed to have HSV-1 and HSV-2, respectively. Because it can be transmitted through any intimate contact, it is one of the most common sexually transmitted infections.

Symptoms

Many of those who are infected never develop symptoms. Symptoms, when they occur, may include watery blisters in the skin or mucous membranes of the mouth, lips, nose, or genitals. Lesions heal with a scab characteristic of herpetic disease. Sometimes, the viruses cause mild or atypical symptoms during outbreaks. However, they can also cause more troublesome forms of herpes simplex. As neurotropic and neuroinvasive viruses, HSV-1 and -2 persist in the body by hiding from the immune system in the cell bodies of neurons. After the initial or primary infection, some infected people experience sporadic episodes of viral reactivation or outbreaks. In an outbreak, the virus in a nerve cell becomes active and is transported via the neuron's axon to the skin, where virus replication and shedding occur and cause new sores.

Transmission

HSV-1 and HSV-2 are transmitted by contact with an infected person who has reactivations of the virus. HSV-2 is periodically shed in the human genital tract, most often asymptomatically. Most sexual transmissions occur during periods of asymptomatic shedding. Asymptomatic reactivation means that the virus causes atypical, subtle, or hard-to-notice symptoms that are not identified as an active herpes infection, so acquiring the virus is possible even if no active HSV blisters or sores are present. In one study, daily genital swab samples found HSV-2 at a median of 12–28% of days among those who have had an outbreak, and 10% of days among those suffering from asymptomatic infection, with many of these episodes occurring without visible outbreak ("subclinical shedding").

In another study, 73 subjects were randomized to receive valaciclovir 1 g daily or placebo for 60 days each in a two-way crossover design. A daily swab of the genital area was self-collected for HSV-2 detection by polymerase chain reaction, to compare the effect of valaciclovir versus placebo on asymptomatic viral shedding in immunocompetent, HSV-2 seropositive subjects without a history of symptomatic genital herpes infection. The study found that valaciclovir significantly reduced shedding during subclinical days compared to placebo, showing a 71% reduction; 84% of subjects had no shedding while receiving valaciclovir versus 54% of subjects on placebo. About 88% of patients treated with valaciclovir had no recognized signs or symptoms versus 77% for placebo.

For HSV-2, subclinical shedding may account for most of the transmission. Studies on discordant partners (one infected with HSV-2, one not) show that the transmission rate is approximately 5 per 10,000 sexual contacts. Atypical symptoms are often attributed to other causes, such as a yeast infection. HSV-1 is often acquired orally during childhood. It may also be sexually transmitted, including contact with saliva, such as kissing and mouth-to-genital contact (oral sex). HSV-2 is primarily a sexually transmitted infection, but rates of HSV-1 genital infections are increasing.

Both viruses may also be transmitted vertically during childbirth. However, the risk of infection transmission is minimal if the mother has no symptoms or exposed blisters during delivery. The risk is considerable when the mother is infected with the virus for the first time during late pregnancy. Contrary to popular myths, herpes cannot be transmitted from surfaces such as toilet seats because the herpes virus begins to die immediately after leaving the body.

Herpes simplex viruses can affect areas of skin exposed to contact with an infected person (although shaking hands with an infected person does not transmit this disease). An example of this is herpetic whitlow, which is a herpes infection on the fingers. This was a common affliction of dental surgeons prior to the routine use of gloves when conducting treatment on patients.

Infection of HSV-2 increases the risk of acquiring HIV.

Virology

Viral structure

Play media

A three-dimensional reconstruction and animation of a tail-like assembly on HSV-1 capsid

 

3D reconstruction of the HSV-1 capsid

 

Herpes Simplex Virus 2

Animal herpes viruses all share some common properties. The structure of herpes viruses consists of a relatively large, double-stranded, linear DNA genome encased within an icosahedral protein cage called the capsid, which is wrapped in a lipid bilayer called the envelope. The envelope is joined to the capsid by means of a tegument. This complete particle is known as the virion. HSV-1 and HSV-2 each contain at least 74 genes (or open reading frames, ORFs) within their genomes, although speculation over gene crowding allows as many as 84 unique protein coding genes by 94 putative ORFs. These genes encode a variety of proteins involved in forming the capsid, tegument and envelope of the virus, as well as controlling the replication and infectivity of the virus. These genes and their functions are summarized in the table below.

The genomes of HSV-1 and HSV-2 are complex and contain two unique regions called the long unique region (U_L) and the short unique region (U_S). Of the 74 known ORFs, U_L contains 56 viral genes, whereas U_S contains only 12. Transcription of HSV genes is catalyzed by RNA polymerase II of the infected host. Immediate early genes, which encode proteins that regulate the expression of early and late viral genes, are the first to be expressed following infection. Early gene expression follows, to allow the synthesis of enzymes involved in DNA replication and the production of certain envelope glycoproteins. Expression of late genes occurs last; this group of genes predominantly encode proteins that form the virion particle.

Five proteins from (U_L) form the viral capsid - UL6, UL18, UL35, UL38, and the major capsid protein UL19.

Cellular entry

A simplified diagram of HSV replication

Entry of HSV into a host cell involves several glycoproteins on the surface of the enveloped virus binding to their transmembrane receptors on the cell surface. Many of these receptors are then pulled inwards by the cell, which is thought to open a ring of three gHgL heterodimers stabilizing a compact conformation of the gB glycoprotein, so that it springs out and punctures the cell membrane. The envelope covering the virus particle then fuses with the cell membrane, creating a pore through which the contents of the viral envelope enters the host cell.

The sequential stages of HSV entry are analogous to those of other viruses. At first, complementary receptors on the virus and the cell surface bring the viral and cell membranes into proximity. Interactions of these molecules then form a stable entry pore through which the viral envelope contents are introduced to the host cell. The virus can also be endocytosed after binding to the receptors, and the fusion could occur at the endosome. In electron micrographs, the outer leaflets of the viral and cellular lipid bilayers have been seen merged; this hemifusion may be on the usual path to entry or it may usually be an arrested state more likely to be captured than a transient entry mechanism.

In the case of a herpes virus, initial interactions occur when two viral envelope glycoprotein called glycoprotein C (gC) and glycoprotein B (gB) bind to a cell surface particle called heparan sulfate. Next, the major receptor binding protein, glycoprotein D (gD), binds specifically to at least one of three known entry receptors. These cell receptors include herpesvirus entry mediator (HVEM), nectin-1 and 3-O sulfated heparan sulfate. The nectin receptors usually produce cell-cell adhesion, to provide a strong point of attachment for the virus to the host cell. These interactions bring the membrane surfaces into mutual proximity and allow for other glycoproteins embedded in the viral envelope to interact with other cell surface molecules. Once bound to the HVEM, gD changes its conformation and interacts with viral glycoproteins H (gH) and L (gL), which form a complex. The interaction of these membrane proteins may result in a hemifusion state. gB interaction with the gH/gL complex creates an entry pore for the viral capsid. gB interacts with glycosaminoglycans on the surface of the host cell.

Genetic inoculation

After the viral capsid enters the cellular cytoplasm, it is transported to the cell nucleus. Once attached to the nucleus at a nuclear entry pore, the capsid ejects its DNA contents via the capsid portal. The capsid portal is formed by 12 copies of portal protein, UL6, arranged as a ring; the proteins contain a leucine zipper sequence of amino acids, which allow them to adhere to each other. Each icosahedral capsid contains a single portal, located in one vertex. The DNA exits the capsid in a single linear segment.

Immune evasion

HSV evades the immune system through interference with MHC class I antigen presentation on the cell surface, by blocking the transporter associated with antigen processing (TAP) induced by the secretion of ICP-47 by HSV. In the host cell, TAP transports digested viral antigen epitope peptides from the cytosol to the endoplasmic reticulum, allowing these epitopes to be combined with MHC class I molecules and presented on the surface of the cell. Viral epitope presentation with MHC class I is a requirement for activation of cytotoxic T-lymphocytes (CTLs), the major effectors of the cell-mediated immune response against virally-infected cells. ICP-47 prevents initiation of a CTL-response against HSV, allowing the virus to survive for a protracted period in the host.

Replication

Micrograph showing the viral cytopathic effect of HSV (multinucleation, ground glass chromatin)

 

Following infection of a cell, a cascade of herpes virus proteins, called immediate-early, early, and late, is produced. Research using flow cytometry on another member of the herpes virus family, Kaposi's sarcoma-associated herpesvirus, indicates the possibility of an additional lytic stage, delayed-late. These stages of lytic infection, particularly late lytic, are distinct from the latency stage. In the case of HSV-1, no protein products are detected during latency, whereas they are detected during the lytic cycle.

The early proteins transcribed are used in the regulation of genetic replication of the virus. On entering the cell, an α-TIF protein joins the viral particle and aids in immediate-early transcription. The virion host shutoff protein (VHS or UL41) is very important to viral replication. This enzyme shuts off protein synthesis in the host, degrades host mRNA, helps in viral replication, and regulates gene expression of viral proteins. The viral genome immediately travels to the nucleus, but the VHS protein remains in the cytoplasm.

The late proteins form the capsid and the receptors on the surface of the virus. Packaging of the viral particles — including the genome, core and the capsid - occurs in the nucleus of the cell. Here, concatemers of the viral genome are separated by cleavage and are placed into formed capsids. HSV-1 undergoes a process of primary and secondary envelopment. The primary envelope is acquired by budding into the inner nuclear membrane of the cell. This then fuses with the outer nuclear membrane, releasing a naked capsid into the cytoplasm. The virus acquires its final envelope by budding into cytoplasmic vesicles.

Latent infection

HSVs may persist in a quiescent but persistent form known as latent infection, notably in neural ganglia. HSV-1 tends to reside in the trigeminal ganglia, while HSV-2 tends to reside in the sacral ganglia, but these are tendencies only, not fixed behavior. During latent infection of a cell, HSVs express latency-associated transcript (LAT) RNA. LAT regulates the host cell genome and interferes with natural cell death mechanisms. By maintaining the host cells, LAT expression preserves a reservoir of the virus, which allows subsequent, usually symptomatic, periodic recurrences or "outbreaks" characteristic of nonlatency. Whether or not recurrences are symptomatic, viral shedding occurs to infect a new host. 

A protein found in neurons may bind to herpes virus DNA and regulate latency. Herpes virus DNA contains a gene for a protein called ICP4, which is an important transactivator of genes associated with lytic infection in HSV-1. Elements surrounding the gene for ICP4 bind a protein known as the human neuronal protein neuronal restrictive silencing factor (NRSF) or human repressor element silencing transcription factor (REST). When bound to the viral DNA elements, histone deacetylation occurs atop the ICP4 gene sequence to prevent initiation of transcription from this gene, thereby preventing transcription of other viral genes involved in the lytic cycle. Another HSV protein reverses the inhibition of ICP4 protein synthesis. ICP0 dissociates NRSF from the ICP4 gene and thus prevents silencing of the viral DNA.

Genome

The HSV genome consists of two unique segments, named unique long (UL) and unique short (US), as well as terminal inverted repeats found to the two ends of them named repeat long (RL) and repeat short (RS). There are also minor "terminal redundancy" (α) elements found on the further ends of RS. The overall arrangement is RL-UL-RL-α-RS-US-RS-α with each pair of repeats inverting each other. The whole sequence is then encapsuled in a terminal direct repeat. The long and short parts each have their own origins of replication, with OriL located between UL28 and UL30 and OriS located in a pair nearthe RS. As the L and S segments can be assembled in any direction, they can be inverted relative to each other freely, forming various linear isomers.

The open reading frames (ORFs) of HSV

ORF	Protein alias	HSV-1	HSV-2	Function/description
Repeat long (RL)
ICP0/RL2	ICP0; IE110; α0	P08393	P28284	E3 ubiquitin ligase that activates viral gene transcription by opposing chromatinization of the viral genome and counteracts intrinsic- and interferon-based antiviral responses.
RL1	RL1; ICP34.5	O12396		Neurovirulence factor. Antagonizes PKR by de-phosphorylating eIF4a. Binds to BECN1 and inactivates autophagy.
LAT	LRP1, LRP2	P17588 P17589		Latency-associated transcript abd protein products (latency-related protein)
Unique long (UL)
UL1	Glycoprotein L	P10185		Surface and membrane
UL2	UL2	P10186		Uracil-DNA glycosylase
UL3	UL3	P10187		unknown
UL4	UL4	P10188		unknown
UL5	UL5	Q2MGV2		DNA replication
UL6	Portal protein UL-6	P10190		Twelve of these proteins constitute the capsid portal ring through which DNA enters and exits the capsid
UL7	UL7	P10191		Virion maturation
UL8	UL8	P10192		DNA virus helicase-primase complex-associated protein
UL9	UL9	P10193		Replication origin-binding protein
UL10	Glycoprotein M	P04288		Surface and membrane
UL11	UL11	P04289		virion exit and secondary envelopment
UL12	UL12	Q68978		Alkaline exonuclease
UL13	UL13	Q9QNF2		Serine-threonine protein kinase
UL14	UL14	P04291		Tegument protein
UL15	Terminase	P04295		Processing and packaging of DNA
UL16	UL16	P10200		Tegument protein
UL17	UL17	P10201		Processing and packaging DNA
UL18	VP23	P10202		Capsid protein
UL19	VP5	P06491		Major capsid protein
UL20	UL20	P10204		Membrane protein
UL21	UL21	P10205		Tegument protein
UL22	Glycoprotein H	P06477		Surface and membrane
UL23	Thymidine kinase	O55259		Peripheral to DNA replication
UL24	UL24	P10208		unknown
UL25	UL25	P10209		Processing and packaging DNA
UL26	P40; VP24; VP22A; UL26.5 (HHV2 short isoform)	P10210	P89449	Capsid protein
UL27	Glycoprotein B	A1Z0P5		Surface and membrane
UL28	ICP18.5	P10212		Processing and packaging DNA
UL29	UL29; ICP8	Q2MGU6		Major DNA-binding protein
UL30	DNA polymerase	Q4ACM2		DNA replication
UL31	UL31	Q25BX0		Nuclear matrix protein
UL32	UL32	P10216		Envelope glycoprotein
UL33	UL33	P10217		Processing and packaging DNA
UL34	UL34	P10218		Inner nuclear membrane protein
UL35	VP26	P10219		Capsid protein
UL36	UL36	P10220		Large tegument protein
UL37	UL37	P10216		Capsid assembly
UL38	UL38; VP19C	P32888		Capsid assembly and DNA maturation
UL39	UL39; RR-1; ICP6	P08543		Ribonucleotide reductase (large subunit)
UL40	UL40; RR-2	P06474		Ribonucleotide reductase (small subunit)
UL41	UL41; VHS	P10225		Tegument protein; virion host shutoff
UL42	UL42	Q4H1G9		DNA polymerase processivity factor
UL43	UL43	P10227		Membrane protein
UL44	Glycoprotein C	P10228		Surface and membrane
UL45	UL45	P10229		Membrane protein; C-type lectin
UL46	VP11/12	P08314		Tegument proteins
UL47	UL47; VP13/14	P10231		Tegument protein
UL48	VP16 (Alpha-TIF)	P04486		Virion maturation; activate IE genes by interacting with the cellular transcription factors Oct-1 and HCF. Binds to the sequence 5'TAATGARAT3'.
UL49	UL49A	O09800		Envelope protein
UL50	UL50	P10234		dUTP diphosphatase
UL51	UL51	P10234		Tegument protein
UL52	UL52	P10236		DNA helicase/primase complex protein
UL53	Glycoprotein K	P68333		Surface and membrane
UL54	IE63; ICP27	P10238		Transcriptional regulation and inhibition of the STING signalsome
UL55	UL55	P10239		Unknown
UL56	UL56	P10240		Unknown
Inverted repeat long (IRL)
Inverted repeat short (IRS)
Unique short (US)
US1	ICP22; IE68	P04485		Viral replication
US2	US2	P06485		Unknown
US3	US3	P04413		Serine/threonine-protein kinase
US4	Glycoprotein G	P06484		Surface and membrane
US5	Glycoprotein J	P06480		Surface and membrane
US6	Glycoprotein D	A1Z0Q5		Surface and membrane
US7	Glycoprotein I	P06487		Surface and membrane
US8	Glycoprotein E	Q703F0		Surface and membrane
US9	US9	P06481		Tegument protein
US10	US10	P06486		Capsid/Tegument protein
US11	US11; Vmw21	P56958		Binds DNA and RNA
US12	Infected cell protein 47｜ICP47; IE12	P03170		Inhibits MHC class I pathway by preventing binding of antigen to TAP
Terminal repeat short (TRS)
RS1	ICP4; IE175	P08392		Major transcriptional activator. Essential for progression beyond the immediate-early phase of infection. IEG transcription repressor.

Evolution

The herpes simplex 1 genomes can be classified into six clades. Four of these occur in East Africa, one in East Asia and one in Europe and North America. This suggests that the virus may have originated in East Africa. The most recent common ancestor of the Eurasian strains appears to have evolved ~60,000 years ago. The East Asian HSV-1 isolates have an unusual pattern that is currently best explained by the two waves of migration responsible for the peopling of Japan.  Herpes simplex 2 genomes can be divided into two groups: one is globally distributed and the other is mostly limited to sub Saharan Africa. The globably distributed genotype has undergone four ancient recombinations with herpes simplex 1. It has also been reported that HSV-1 and HSV-2 can have contemporary and stable recombination events in hosts simultaneously infected with both pathogens. All of the cases are HSV-2 acquiring parts of the HSV-1 genome, sometimes changing parts of its antigen epitope in the process.

The mutation rate has been estimated to be ~1.38×10⁻⁷ substitutions/site/year.^[45] In clinical setting, the mutations in either the thymidine kinase gene or DNA polymerase gene has caused resistance to aciclovir. However, most of the mutations occur in the thymidine kinase gene rather than the DNA polymerase gene.

Another analysis has estimated the mutation rate in the herpes simplex 1 genome to be 1.82×10⁻⁸ nucleotide substitution per site per year. This analysis placed the most recent common ancestor of this virus ~710,000 years ago.

Herpes simplex 1 and 2 diverged about 6 million years ago.

Treatment

The herpes viruses establish lifelong infections (thus cannot be eradicated from the body). Because the virus is a foreign pathogen, a human body's immune system as well as its specialty antigen naturally diminishes the virus.

Treatment usually involves general-purpose antiviral drugs that interfere with viral replication, reduce the physical severity of outbreak-associated lesions, and lower the chance of transmission to others. Studies of vulnerable patient populations have indicated that daily use of antivirals such as aciclovir and valaciclovir can reduce reactivation rates. The extensive use of antiherpetic drugs has led to the development of drug resistance, which in turn leads to treatment failure. Therefore, new sources of drugs are broadly investigated to defeat the problem. In January 2020, a comprehensive review article was published that demonstrated the effectiveness of natural products as promising anti-HSV drugs.

Pyrithione, a Zinc Ionophore, show antiviral activity against Herpes simplex virus.

Alzheimer's disease

It was reported, in 1979, that there is a possible link between HSV-1 and Alzheimer's disease, in people with the epsilon4 allele of the gene APOE. HSV-1 appears to be particularly damaging to the nervous system and increases one's risk of developing Alzheimer's disease. The virus interacts with the components and receptors of lipoproteins, which may lead to the development of Alzheimer's disease. This research identifies HSVs as the pathogen most clearly linked to the establishment of Alzheimer's. According to a study done in 1997, without the presence of the gene allele, HSV-1 does not appear to cause any neurological damage or increase the risk of Alzheimer's. However, a more recent prospective study published in 2008 with a cohort of 591 people showed a statistically significant difference between patients with antibodies indicating recent reactivation of HSV and those without these antibodies in the incidence of Alzheimer's disease, without direct correlation to the APOE-epsilon4 allele.

The trial had a small sample of patients who did not have the antibody at baseline, so the results should be viewed as highly uncertain. In 2011 Manchester University scientists showed that treating HSV1-infected cells with antiviral agents decreased the accumulation of β-amyloid and tau protein, and also decreased HSV-1 replication.

A 2018 retrospective study from Taiwan on 33,000 patients found that being infected with herpes simplex virus increased the risk of dementia 2.56 times (95% CI: 2.3-2.8) in patients not receiving anti-herpetic medications (2.6 times for HSV-1 infections and 2.0 times for HSV-2 infections). However, HSV-infected patients who were receiving anti-herpetic medications (acyclovir, famciclovir, ganciclovir, idoxuridine, penciclovir, tromantadine, valaciclovir, or valganciclovir) showed no elevated risk of dementia compared to patients uninfected with HSV.

Multiplicity reactivation

Multiplicity reactivation (MR) is the process by which viral genomes containing inactivating damage interact within an infected cell to form a viable viral genome. MR was originally discovered with the bacterial virus bacteriophage T4, but was subsequently also found with pathogenic viruses including influenza virus, HIV-1, adenovirus simian virus 40, vaccinia virus, reovirus, poliovirus and herpes simplex virus.

When HSV particles are exposed to doses of a DNA damaging agent that would be lethal in single infections, but are then allowed to undergo multiple infection (i.e. two or more viruses per host cell), MR is observed. Enhanced survival of HSV-1 due to MR occurs upon exposure to different DNA damaging agents, including methyl methanesulfonate, trimethylpsoralen (which causes inter-strand DNA cross-links), and UV light. After treatment of genetically marked HSV with trimethylpsoralen, recombination between the marked viruses increases, suggesting that trimethylpsoralen damage stimulates recombination. MR of HSV appears to partially depend on the host cell recombinational repair machinery since skin fibroblast cells defective in a component of this machinery (i.e. cells from Bloom's syndrome patients) are deficient in MR.

These observations suggest that MR in HSV infections involves genetic recombination between damaged viral genomes resulting in production of viable progeny viruses. HSV-1, upon infecting host cells, induces inflammation and oxidative stress. Thus it appears that the HSV genome may be subjected to oxidative DNA damage during infection, and that MR may enhance viral survival and virulence under these conditions.

Use as an anti-cancer agent

Modified Herpes simplex virus is considered as a potential therapy for cancer and has been extensively clinically tested to assess its oncolytic (cancer killing) ability. Interim overall survival data from Amgen's phase 3 trial of a genetically-attenuated herpes virus suggests efficacy against melanoma.

Use in neuronal connection tracing

Herpes simplex virus is also used as a transneuronal tracer defining connections among neurons by virtue of traversing synapses.

Other related outcomes

Herpes simplex virus is likely the most common cause of Mollaret's meningitis. In worst-case scenarios, it can lead to a potentially fatal case of herpes simplex encephalitis.

Research

There exist commonly used vaccines to some herpesviruses, but only veterinary, such as HVT/LT (Turkey herpesvirus vector laryngotracheitis vaccine). However, it prevents atherosclerosis (which histologically mirrors atherosclerosis in humans) in target animals vaccinated.

Adaptive immune system

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Adaptive_immune_system 

A scanning electron microscope image of a single human lymphocyte

The adaptive immune system, also referred as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminates pathogens by preventing their growth. The acquired immune system is one of the two main immunity strategies found in vertebrates (the other being the innate immune system).

Acquired immunity creates immunological memory after an initial response to a specific pathogen, and leads to an enhanced response to subsequent encounters with that pathogen. This process of acquired immunity is the basis of vaccination. Like the innate system, the acquired system includes both humoral immunity components and cell-mediated immunity components. 

Google Ngram of "acquired immunity " vs. "adaptive immunity". The peak for "adaptive" in the 1960s reflects its introduction to immunology by Robert A. Good and use by colleagues; the explosive increase in the 1990s was correlated with the use of the phrase "innate immunity".

Unlike the innate immune system, the acquired immune system is highly specific to a particular pathogen. Acquired immunity can also provide long-lasting protection; for example, someone who recovers from measles is now protected against measles for their lifetime. In other cases it does not provide lifetime protection; for example, chickenpox. The acquired system response destroys invading pathogens and any toxic molecules they produce. Sometimes the acquired system is unable to distinguish harmful from harmless foreign molecules; the effects of this may be hayfever, asthma or any other allergy. 

Antigens are any substances that elicit the acquired immune response (whether adaptive or maladaptive to the organism). 

The cells that carry out the acquired immune response are white blood cells known as lymphocytes. Two main activities—antibody responses and cell mediated immune response—are also carried out by two different lymphocytes (B cells and T cells). In antibody responses, B cells are activated to secrete antibodies, which are proteins also known as immunoglobulins. Antibodies travel through the bloodstream and bind to the foreign antigen causing it to inactivate, which does not allow the antigen to bind to the host.

In acquired immunity, pathogen-specific receptors are "acquired" during the lifetime of the organism (whereas in innate immunity pathogen-specific receptors are already encoded in the germline). The acquired response is called "adaptive" because it prepares the body's immune system for future challenges (though it can actually also be maladaptive when it results in autoimmunity).

The system is highly adaptable because of somatic hypermutation (a process of accelerated somatic mutations), and V(D)J recombination (an irreversible genetic recombination of antigen receptor gene segments). This mechanism allows a small number of genes to generate a vast number of different antigen receptors, which are then uniquely expressed on each individual lymphocyte. Since the gene rearrangement leads to an irreversible change in the DNA of each cell, all progeny (offspring) of that cell inherit genes that encode the same receptor specificity, including the memory B cells and memory T cells that are the keys to long-lived specific immunity.

A theoretical framework explaining the workings of the acquired immune system is provided by immune network theory. This theory, which builds on established concepts of clonal selection, is being applied in the search for an HIV vaccine.

Naming

The term "adaptive" was first used by Robert Good in reference to antibody responses in frogs as a synonym for "acquired immune response" in 1964. Good acknowledged he used the terms as synonyms but explained only that he "preferred" to use the term "adaptive". He might have been thinking of the then not implausible theory of antibody formation in which antibodies were plastic and could adapt themselves to the molecular shape of antigens, and/or to the concept of "adaptive enzymes" as described by Monod in bacteria, that is, enzymes whose expression could be induced by their substrates. The phrase was used almost exclusively by Good and his students and a few other immunologists working with marginal organisms until the 1990s when it became widely used in tandem with the term "innate immunity" which became a popular subject after the discovery of the Toll receptor system in Drosophila, a previously marginal organism for the study of immunology. The term "adaptive" as used in immunology is problematic as acquired immune responses can be both adaptive and maladaptive in the physiological sense. Indeed, both acquired and innate immune responses can be both adaptive and maladaptive in the evolutionary sense. Most textbooks today, following the early use by Janeway, use "adaptive" almost exclusively and noting in glossaries that the term is synonymous with "acquired".

The classic sense of "acquired immunity" came to mean, since Tonegawa's discovery, "antigen-specific immunity mediated by somatic gene rearrangements that create clone-defining antigen receptors". In the last decade, the term "adaptive" has been increasingly applied to another class of immune response not so-far associated with somatic gene rearrangements. These include expansion of natural killer (NK) cells with so-far unexplained specificity for antigens, expansion of NK cells expressing germ-line encoded receptors, and activation of other innate immune cells to an activated state that confers a short-term "immune memory". In this sense, "adaptive immunity" more closely resembles the concept of "activated state" or "heterostasis", thus returning in sense to the physiological sense of "adaptation" to environmental changes.

Functions

Overview of the processes involved in the primary immune response

 

Acquired immunity is triggered in vertebrates when a pathogen evades the innate immune system and (1) generates a threshold level of antigen and (2) generates "stranger" or "danger" signals activating dendritic cells.

The major functions of the acquired immune system include:

• Recognition of specific "non-self" antigens in the presence of "self", during the process of antigen presentation.
• Generation of responses that are tailored to maximally eliminate specific pathogens or pathogen-infected cells.
• Development of immunological memory, in which pathogens are "remembered" through memory B cells and memory T cells.

In humans, it takes 4-7 days for the adaptive immune system to mount a significant response.

Lymphocytes

The cells of the acquired immune system are T and B lymphocytes; lymphocytes are a subset of leukocyte. B cells and T cells are the major types of lymphocytes. The human body has about 2 trillion lymphocytes, constituting 20–40% of white blood cells (WBCs); their total mass is about the same as the brain or liver. The peripheral blood contains 2% of circulating lymphocytes; the rest move within the tissues and lymphatic system.

B cells and T cells are derived from the same multipotent hematopoietic stem cells, and are morphologically indistinguishable from one another until after they are activated. B cells play a large role in the humoral immune response, whereas T cells are intimately involved in cell-mediated immune responses. In all vertebrates except Agnatha, B cells and T cells are produced by stem cells in the bone marrow.

T progenitors migrate from the bone marrow to the thymus where they are called thymocytes and where they develop into T cells. In humans, approximately 1–2% of the lymphocyte pool recirculates each hour to optimize the opportunities for antigen-specific lymphocytes to find their specific antigen within the secondary lymphoid tissues. In an adult animal, the peripheral lymphoid organs contain a mixture of B and T cells in at least three stages of differentiation:

• naive B and naive T cells (cells that have not matured), left the bone marrow or thymus, have entered the lymphatic system, but have yet to encounter their cognate antigen,
• effector cells that have been activated by their cognate antigen, and are actively involved in eliminating a pathogen.
• memory cells – the survivors of past infections.

Antigen presentation

Acquired immunity relies on the capacity of immune cells to distinguish between the body's own cells and unwanted invaders. The host's cells express "self" antigens. These antigens are different from those on the surface of bacteria or on the surface of virus-infected host cells ("non-self" or "foreign" antigens). The acquired immune response is triggered by recognizing foreign antigen in the cellular context of an activated dendritic cell.

With the exception of non-nucleated cells (including erythrocytes), all cells are capable of presenting antigen through the function of major histocompatibility complex (MHC) molecules. Some cells are specially equipped to present antigen, and to prime naive T cells. Dendritic cells, B-cells, and macrophages are equipped with special "co-stimulatory" ligands recognized by co-stimulatory receptors on T cells, and are termed professional antigen-presenting cells (APCs). 

Several T cells subgroups can be activated by professional APCs, and each type of T cell is specially equipped to deal with each unique toxin or microbial pathogen. The type of T cell activated, and the type of response generated, depends, in part, on the context in which the APC first encountered the antigen.

Exogenous antigens

Antigen presentation stimulates T cells to become either "cytotoxic" CD8+ cells or "helper" CD4+ cells.

Dendritic cells engulf exogenous pathogens, such as bacteria, parasites or toxins in the tissues and then migrate, via chemotactic signals, to the T cell-enriched lymph nodes. During migration, dendritic cells undergo a process of maturation in which they lose most of their ability to engulf other pathogens, and develop an ability to communicate with T-cells. The dendritic cell uses enzymes to chop the pathogen into smaller pieces, called antigens. In the lymph node, the dendritic cell displays these non-self antigens on its surface by coupling them to a receptor called the major histocompatibility complex, or MHC (also known in humans as human leukocyte antigen (HLA)). This MHC: antigen complex is recognized by T-cells passing through the lymph node. Exogenous antigens are usually displayed on MHC class II molecules, which activate CD4+T helper cells.

Endogenous antigens

Endogenous antigens are produced by intracellular bacteria and viruses replicating within a host cell. The host cell uses enzymes to digest virally associated proteins, and displays these pieces on its surface to T-cells by coupling them to MHC. Endogenous antigens are typically displayed on MHC class I molecules, and activate CD8+ cytotoxic T-cells. With the exception of non-nucleated cells (including erythrocytes), MHC class I is expressed by all host cells.

T lymphocytes

CD8+ T lymphocytes and cytotoxicity

Cytotoxic T cells (also known as TC, killer T cell, or cytotoxic T-lymphocyte (CTL)) are a sub-group of T cells that induce the death of cells that are infected with viruses (and other pathogens), or are otherwise damaged or dysfunctional.

 

Naive cytotoxic T cells are activated when their T-cell receptor (TCR) strongly interacts with a peptide-bound MHC class I molecule. This affinity depends on the type and orientation of the antigen/MHC complex, and is what keeps the CTL and infected cell bound together. Once activated, the CTL undergoes a process called clonal selection, in which it gains functions and divides rapidly to produce an army of “armed” effector cells. Activated CTL then travels throughout the body searching for cells that bear that unique MHC Class I + peptide.

When exposed to these infected or dysfunctional somatic cells, effector CTL release perforin and granulysin: cytotoxins that form pores in the target cell's plasma membrane, allowing ions and water to flow into the infected cell, and causing it to burst or lyse. CTL release granzyme, a serine protease encapsulated in a granule that enters cells via pores to induce apoptosis (cell death). To limit extensive tissue damage during an infection, CTL activation is tightly controlled and in general requires a very strong MHC/antigen activation signal, or additional activation signals provided by "helper" T-cells (see below).

On resolution of the infection, most effector cells die and phagocytes clear them away—but a few of these cells remain as memory cells. On a later encounter with the same antigen, these memory cells quickly differentiate into effector cells, dramatically shortening the time required to mount an effective response.

Helper T-cells

The T lymphocyte activation pathway. T cells contribute to immune defenses in two major ways: some direct and regulate immune responses; others directly attack infected or cancerous cells.

 

CD4+ lymphocytes, also called "helper" T cells, are immune response mediators, and play an important role in establishing and maximizing the capabilities of the acquired immune response. These cells have no cytotoxic or phagocytic activity; and cannot kill infected cells or clear pathogens, but, in essence "manage" 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 activation of a naive helper T-cell causes it to release cytokines, which influences the activity of many cell types, including the APC (Antigen-Presenting Cell) that activated it. Helper T-cells require a much milder activation stimulus than cytotoxic T cells. Helper T cells can provide extra signals that "help" activate cytotoxic cells.

Th1 and Th2: helper T cell responses

Classically, two types of effector CD4⁺ T helper cell responses can be induced by a professional APC, designated Th1 and Th2, each designed to eliminate different types of pathogens. The factors that dictate whether an infection triggers a Th1 or Th2 type response are not fully understood, but the response generated does play an important role in the clearance of different pathogens.

The Th1 response is characterized by the production of Interferon-gamma, which activates the bactericidal activities of macrophages, and induces B cells to make opsonizing (marking for phagocytosis) and complement-fixing antibodies, and leads to cell-mediated immunity. In general, Th1 responses are more effective against intracellular pathogens (viruses and bacteria that are inside host cells).

The Th2 response is characterized by the release of Interleukin 5, which induces eosinophils in the clearance of parasites. Th2 also produce Interleukin 4, which facilitates B cell isotype switching. In general, Th2 responses are more effective against extracellular bacteria, parasites including helminths and toxins. Like cytotoxic T cells, most of the CD4⁺ helper cells die on resolution of infection, with a few remaining as CD4⁺ memory cells.

Increasingly, there is strong evidence from mouse and human-based scientific studies of a broader diversity in CD4⁺ effector T helper cell subsets. Regulatory T (Treg) cells, have been identified as important negative regulators of adaptive immunity as they limit and suppresses the immune system to control aberrant immune responses to self-antigens; an important mechanism in controlling the development of autoimmune diseases.  Follicular helper T (Tfh) cells are another distinct population of effector CD4⁺ T cells that develop from naive T cells post-antigen activation. Tfh cells are specialized in helping B cell humoral immunity as they are uniquely capable of migrating to follicular B cells in secondary lymphoid organs and provide them positive paracrine signals to enable the generation and recall production of high-quality affinity-matured antibodies. Similar to Tregs, Tfh cells also play a role in immunological tolerance as an abnormal expansion of Tfh cell numbers can lead to unrestricted autoreactive antibody production causing severe systemic autoimmune disorders.

The relevance of CD4⁺ T helper cells is highlighted during an HIV infection. HIV is able to subvert the immune system by specifically attacking the CD4⁺ T cells, precisely the cells that could drive the clearance of the virus, but also the cells that drive immunity against all other pathogens encountered during an organism's lifetime.

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 characteristics of helper T cells, cytotoxic T cells and natural killer cells. Like other 'unconventional' T cell subsets bearing invariant TCRs, such as CD1d-restricted natural killer T cells, γδ T cells exhibit characteristics that place them at the border between innate and acquired immunity. On one hand, γδ T cells may be considered a component of adaptive immunity in that they rearrange TCR genes via V(D)J recombination, which also produces junctional diversity, and develop a memory phenotype. On the other hand, however, the various subsets may also be considered part of the innate immune system where a restricted TCR or NK receptors may be used as a pattern recognition receptor. For example, according to this paradigm, large numbers of Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted intraepithelial Vδ1 T cells respond to stressed epithelial cells.

B lymphocytes and antibody production

The B lymphocyte activation pathway. B cells function to protect the host by producing antibodies that identify and neutralize foreign objects like bacteria and viruses.

 

B Cells are the major cells involved in the creation of antibodies that circulate in blood plasma and lymph, known as humoral immunity. Antibodies (also known as immunoglobulin, Ig), are large Y-shaped proteins used by the immune system to identify and neutralize foreign objects. In mammals, there are five types of antibody: IgA, IgD, IgE, IgG, and IgM, differing in biological properties; each has evolved to handle different kinds of antigens. Upon activation, B cells produce antibodies, each of which recognize a unique antigen, and neutralizing specific pathogens.

Antigen and antibody binding would cause five different protective mechanisms:

• Agglutination: Reduces number of infectious units to be dealt with
• Activation of complement: Cause inflammation and cell lysis
• Opsonization: Coating antigen with antibody enhances phagocytosis
• Antibody-dependent cell-mediated cytotoxicity: Antibodies attached to target cell cause destruction by macrophages, eosinophils, and NK cells
• Neutralization: Blocks adhesion of bacteria and viruses to mucosa

Like the T cell, B cells express a unique B cell receptor (BCR), in this case, a membrane-bound antibody molecule. All the BCR of any one clone of B cells recognizes and binds to only one particular antigen. A critical difference between B cells and T cells is how each cell "sees" an antigen. T cells recognize their cognate antigen in a processed form – as a peptide in the context of an MHC molecule, whereas B cells recognize antigens in their native form. Once a B cell encounters its cognate (or specific) antigen (and receives additional signals from a helper T cell (predominately Th2 type)), it further differentiates into an effector cell, known as a plasma cell.

Plasma cells are short-lived cells (2–3 days) that secrete antibodies. These antibodies bind to antigens, making them easier targets for phagocytes, and trigger the complement cascade. About 10% of plasma cells survive to become long-lived antigen-specific memory B cells. Already primed to produce specific antibodies, these cells can be called upon to respond quickly if the same pathogen re-infects the host, while the host experiences few, if any, symptoms.

Alternative systems

In jawless vertebrates

Primitive jawless vertebrates, such as the lamprey and hagfish, have an adaptive immune system that shows 3 different cell lineages, each sharing a common origin with B cells, αβ T cells, and innate-like γΔ T cells.  Instead of the classical antibodies and T cell receptors, these animals possess a large array of molecules called variable lymphocyte receptors (VLRs for short) 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.

In insects

For a long time it was thought that insects and other invertebrates possess only innate immune system. However, in recent years some of the basic hallmarks of adaptive immunity have been discovered in insects. Those traits are immune memory and specificity. Although the hallmarks are present the mechanisms are different from those in vertebrates.

Immune memory in insects was discovered through the phenomenon of priming. When insects are exposed to non-lethal dose or heat killed bacteria they are able to develop a memory of that infection that allows them to withstand otherwise lethal dose of the same bacteria they were exposed to before. Unlike in vertebrates, insects do not possess cells specific for adaptive immunity. Instead those mechanisms are mediated by hemocytes. Hemocytes function similarly to phagocytes and after priming they are able to more effectively recognize and engulf the pathogen. It was also shown that it is possible to transfer the memory into offspring. For example, in honeybees if the queen is infected with bacteria then the newly born workers have enhanced abilities in fighting with the same bacteria. Other experimental model based on red flour beetle also showed pathogen specific primed memory transfer into offspring from both mothers and fathers.

Most commonly accepted theory of the specificity is based on Dscam gene. Dscam gene also known as Down syndrome cell adhesive molecule is a gene that contains 3 variable Ig domains. Those domains can be alternatively spliced reaching high numbers of variations. It was shown that after exposure to different pathogens there are different splice forms of dscam produced. After the animals with different splice forms are exposed to the same pathogen only the individuals with the splice form specific for that pathogen survive.

Other mechanisms supporting the specificity of insect immunity is RNA interference (RNAi). RNAi is a form of antiviral immunity with high specificity. It has several different pathways that all end with the virus being unable to replicate. One of the pathways is siRNA in which long double stranded RNA is cut into pieces that serve as templates for protein complex Ago2-RISC that finds and degrades complementary RNA of the virus. MiRNA pathway in cytoplasm binds to Ago1-RISC complex and functions as a template for viral RNA degradation. Last one is piRNA where small RNA binds to the Piwi protein family and controls transposones and other mobile elements. Despite the research the exact mechanisms responsible for immune priming and specificity in insects are not well described.

Immunological memory

When B cells and T cells are activated some become memory B cells and some memory T cells. Throughout the lifetime of an animal these memory cells form a database of effective B and T lymphocytes. Upon interaction with a previously encountered antigen, the appropriate memory cells are selected and activated. In this manner, the second and subsequent exposures to an antigen produce a stronger and faster immune response. This is "adaptive" in the sense that the body's immune system prepares itself for future challenges, but is "maladaptive" of course if the receptors are autoimmune. Immunological memory can be in the form of either passive short-term memory or active long-term memory.

Passive memory

Passive memory is usually short-term, lasting between a few days and several months. Newborn infants have had no prior exposure to microbes and are particularly vulnerable to infection. Several layers of passive protection are provided by the mother. In utero, maternal IgG is transported directly across the placenta, so that, at birth, human babies have high levels of antibodies, with the same range of antigen specificities as their mother. Breast milk contains antibodies (mainly IgA) that are transferred to the gut of the infant, protecting 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. Short-term passive immunity can also be transferred artificially from one individual to another via antibody-rich serum.

Active memory

In general, active immunity is long-term and can be acquired by infection followed by B cell and T cell activation, or artificially acquired by vaccines, in a process called immunization.

Immunization

Historically, infectious disease has been the leading cause of death in the human population. Over the last century, two important factors have been developed to combat their spread: sanitation and immunization. Immunization (commonly referred to as vaccination) is the deliberate induction of an immune response, and represents the single most effective manipulation of the immune system that scientists have developed. Immunizations are successful because they utilize the immune system's natural specificity as well as its inducibility.

The principle behind immunization is to introduce an antigen, derived from a disease-causing organism, that stimulates the immune system to develop protective immunity against that organism, but that does not itself cause the pathogenic effects of that organism. An antigen (short for antibody generator), is defined as any substance that binds to a specific antibody and elicits an adaptive immune response.

Most viral vaccines are based on live attenuated viruses, whereas many bacterial vaccines are based on acellular components of microorganisms, including harmless toxin components. Many antigens derived from acellular vaccines do not strongly induce an adaptive response, and most bacterial vaccines require the addition of adjuvants that activate the antigen-presenting cells of the innate immune system to enhance immunogenicity.

Immunological diversity

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.

 

Most large molecules, including virtually all proteins and many polysaccharides, can serve as antigens. The parts of an antigen that interact with an antibody molecule or a lymphocyte receptor, are called epitopes, or antigenic determinants. Most antigens contain a variety of epitopes and can stimulate the production of antibodies, specific T cell responses, or both. A very small proportion (less than 0.01%) of the total lymphocytes are able to bind to a particular antigen, which suggests that only a few cells respond to each antigen.

For the acquired response to "remember" and eliminate a large number of pathogens the immune system must be able to distinguish between many different antigens, and the receptors that recognize antigens must be produced in a huge variety of configurations, in essence one receptor (at least) for each different pathogen that might ever be encountered. Even in the absence of antigen stimulation, a human can produce more than 1 trillion different antibody molecules. Millions of genes would be required to store the genetic information that produces these receptors, but, the entire human genome contains fewer than 25,000 genes.

Myriad receptors are produced through a process known as clonal selection. According to the clonal selection theory, at birth, an animal randomly generates a vast diversity of lymphocytes (each bearing a unique antigen receptor) from information encoded in a small family of genes. To generate each unique antigen receptor, these genes have undergone a process called V(D)J recombination, or combinatorial diversification, in which one gene segment recombines with other gene segments to form a single unique gene. This assembly process generates the enormous diversity of receptors and antibodies, before the body ever encounters antigens, and enables the immune system to respond to an almost unlimited diversity of antigens. Throughout an animal's lifetime, lymphocytes that can react against the antigens an animal actually encounters are selected for action—directed against anything that expresses that antigen. 

Note that the innate and acquired portions of the immune system work together, not in spite of each other. The acquired arm, B, and T cells couldn't function without the innate system input. T cells are useless without antigen-presenting cells to activate them, and B cells are crippled without T cell help. On the other hand, the innate system would likely be overrun with pathogens without the specialized action of the adaptive immune response.

Acquired immunity during pregnancy

The cornerstone of the immune system is the recognition of "self" versus "non-self". Therefore, the mechanisms that protect the human fetus (which is considered "non-self") from attack by the immune system, are particularly interesting. Although no comprehensive explanation has emerged to explain this mysterious, and often repeated, lack of rejection, two classical reasons may explain how the fetus is tolerated. The first is that the fetus occupies a portion of the body protected by a non-immunological barrier, the uterus, which the immune system does not routinely patrol. The second is that the fetus itself may promote local immunosuppression in the mother, perhaps by a process of active nutrient depletion. A more modern explanation for this induction of tolerance is that specific glycoproteins expressed in the uterus during pregnancy suppress the uterine immune response (see eu-FEDS). 

During pregnancy in viviparous mammals (all mammals except Monotremes), endogenous retroviruses (ERVs) are activated and produced in high quantities during the implantation of the embryo. They are currently known to possess immunosuppressive properties, suggesting a role in protecting the embryo from its mother's immune system. Also, viral fusion proteins cause the formation of the placental syncytium to limit exchange of migratory cells between the developing embryo and the body of the mother (something an epithelium can't do sufficiently, as certain blood cells specialize to insert themselves between adjacent epithelial cells). The immunodepressive action was the initial normal behavior of the virus, similar to HIV. The fusion proteins were a way to spread the infection to other cells by simply merging them with the infected one (HIV does this too). It is believed that the ancestors of modern viviparous mammals evolved after an infection by this virus, enabling the fetus to survive the immune system of the mother.

The human genome project found several thousand ERVs classified into 24 families.

Immune network theory

A theoretical framework explaining the workings of the acquired immune system is provided by immune network theory, based on interactions between idiotypes (unique molecular features of one clonotype, i.e. the unique set of antigenic determinants of the variable portion of an antibody) and 'anti-idiotypes' (antigen receptors that react with the idiotype as if it were a foreign antigen). This theory, which builds on the existing clonal selection hypothesis and since 1974 has been developed mainly by Niels Jerne and Geoffrey W. Hoffmann, is seen as being relevant to the understanding of the HIV pathogenesis and the search for an HIV vaccine.

Stimulation of adaptive immunity

One of the most interesting developments in biomedical science during the past few decades has been elucidation of mechanisms mediating innate immunity. One set of innate immune mechanisms is humoral, such as complement activation. Another set comprises pattern recognition receptors such as toll-like receptors, which induce the production of interferons and other cytokines increasing resistance of cells such as monocytes to infections. Cytokines produced during innate immune responses are among the activators of adaptive immune responses. Antibodies exert additive or synergistic effects with mechanisms of innate immunity. Unstable HbS clusters Band-3, a major integral red cell protein; antibodies recognize these clusters and accelerate their removal by phagocytic cells. Clustered Band 3 proteins with attached antibodies activate complement, and complement C3 fragments are opsonins recognized by the CR1 complement receptor on phagocytic cells.

A population study has shown that the protective effect of the sickle-cell trait against falciparum malaria involves the augmentation of acquired as well as innate immune responses to the malaria parasite, illustrating the expected transition from innate to acquired immunity.

Repeated malaria infections strengthen acquired immunity and broaden its effects against parasites expressing different surface antigens. By school age most children have developed efficacious adaptive immunity against malaria. These observations raise questions about mechanisms that favor the survival of most children in Africa while allowing some to develop potentially lethal infections.

In malaria, as in other infections, innate immune responses lead into, and stimulate, adaptive immune responses. The genetic control of innate and acquired immunity is now a large and flourishing discipline. 

Humoral and cell-mediated immune responses limit malaria parasite multiplication, and many cytokines contribute to the pathogenesis of malaria as well as to the resolution of infections.

Evolution

The acquired immune system, which has been best-studied in mammals, originated in jawed fish approximately 500 million years ago. Most of the molecules, cells, tissues, and associated mechanisms of this system of defense are found in cartilaginous fishes. Lymphocyte receptors, Ig and TCR, are found in all jawed vertebrates. The most ancient Ig class, IgM, is membrane-bound and then secreted upon stimulation of cartilaginous fish B cells. Another isotype, shark IgW, is related to mammalian IgD. TCRs, both α/β and γ/δ, are found in all animals from gnathostomes to mammals. The organization of gene segments that undergo gene rearrangement differs in cartilaginous fishes, which have a cluster form as compared to the translocon form in bony fish to mammals. Like TCR and Ig, the MHC is found only in jawed vertebrates. Genes involved in antigen processing and presentation, as well as the class I and class II genes, are closely linked within the MHC of almost all studied species.

Lymphoid cells can be identified in some pre-vertebrate deuterostomes (i.e., sea urchins). These bind antigen with pattern recognition receptors (PRRs) of the innate immune system. In jawless fishes, two subsets of lymphocytes use variable lymphocyte receptors (VLRs) for antigen binding. Diversity is generated by a cytosine deaminase-mediated rearrangement of LRR-based DNA segments. There is no evidence for the recombination-activating genes (RAGs) that rearrange Ig and TCR gene segments in jawed vertebrates. 

The evolution of the AIS, based on Ig, TCR, and MHC molecules, is thought to have arisen from two major evolutionary events: the transfer of the RAG transposon (possibly of viral origin) and two whole genome duplications. Though the molecules of the AIS are well-conserved, they are also rapidly evolving. Yet, a comparative approach finds that many features are quite uniform across taxa. All the major features of the AIS arose early and quickly. Jawless fishes have a different AIS that relies on gene rearrangement to generate diverse immune receptors with a functional dichotomy that parallels Ig and TCR molecules. The innate immune system, which has an important role in AIS activation, is the most important defense system of invertebrates and plants.

Types of acquired immunity

Immunity can be acquired either actively or passively. Immunity is acquired actively when a person is exposed to foreign substances and the immune system responds. Passive immunity is when antibodies are transferred from one host to another. Both actively acquired and passively acquired immunity can be obtained by natural or artificial means.

• Naturally Acquired Active Immunity – when a person is naturally exposed to antigens, becomes ill, then recovers.
• Naturally Acquired Passive Immunity – involves a natural transfer of antibodies from a mother to her infant. The antibodies cross the woman's placenta to the fetus. Antibodies can also be transferred through breast milk with the secretions of colostrum.
• Artificially Acquired Active Immunity – is done by vaccination (introducing dead or weakened antigen to the host's cell).
• Artificially Acquired Passive Immunity – This involves the introduction of antibodies rather than antigens to the human body. These antibodies are from an animal or person who is already immune to the disease.

Naturally acquired	Artificially acquired
Active – Antigen enters the body naturally	Active – Antigens are introduced in vaccines.
Passive – Antibodies pass from mother to fetus via placenta or infant via the mother's milk.	Passive – Preformed antibodies in immune serum are introduced by injection.