Artistic
rendering of the surface of a human dendritic cell illustrating
sheet-like processes that fold back onto the membrane surface. When
exposed to HIV, some researchers believe that these sheets entrap viruses in the vicinity and focus them to contact zones with T cells targeted for infection. These studies were carried out using ion abrasion scanning electron microscopy, a new technology the NIH
has been developing and applying for 3D cellular imaging. Source:
Sriram Subramaniam, National Cancer Institute (NCI) and Donny Bliss,
National Library of Medicine (NLM).
Dendritic cells are present in those tissues that are in contact with the external environment, such as the skin (where there is a specialized dendritic cell type called the Langerhans cell) and the inner lining of the nose, lungs, stomach and intestines. They can also be found in an immature state in the blood. Once activated, they migrate to the lymph nodes where they interact with T cells and B cells to initiate and shape the adaptive immune response. At certain development stages they grow branched projections, the dendrites
that give the cell its name (δένδρον or déndron being Greek for
'tree'). While similar in appearance, these are structures distinct from
the dendrites of neurons. Immature dendritic cells are also called veiled cells, as they possess large cytoplasmic 'veils' rather than dendrites.
The morphology
of dendritic cells results in a very large surface-to-volume ratio.
That is, the dendritic cell has a very large surface area compared to
the overall cell volume.
Conventional dendritic cell (previously called Myeloid dendritic cell) (cDC or mDC)
Most similar to monocytes. mDC are made up of at least two subsets: (1) the more common mDC-1, which is a major stimulator of T cells (2) the extremely rare mDC-2, which may have a function in fighting wound infection
The markers BDCA-2, BDCA-3, and BDCA-4 can be used to discriminate among the types.
Lymphoid and myeloid DCs evolve from lymphoid and myeloid precursors, respectively, and thus are of hematopoietic origin. By contrast, follicular dendritic cells (FDC) are probably of mesenchymal rather than hematopoietic origin and do not express MHC class II, but are so named because they are located in lymphoid follicles and have long "dendritic" processes.
In blood
The
blood DCs are typically identified and enumerated in flow cytometry.
Three types of DCs have been defined in human blood: the CD1c+ myeloid
DCs, the CD141+ myeloid DCs and the CD303+ plasmacytoid DCs. This represents the nomenclature proposed by the nomenclature committee of the International Union of Immunological Societies.
Dendritic cells that circulate in blood do not have all the typical
features of their counterparts in tissue, i.e. they are less mature and
have no dendrites. Still, they can perform complex functions including
chemokine-production (in CD1c+ myeloid DCs), cross-presentation (in CD141+ myeloid DCs), and IFNalpha production (in CD303+ plasmacytoid DCs).
In vitro
In some respects, dendritic cells cultured in vitro do not show the same behaviour or capability as dendritic cells isolated ex vivo. Nonetheless, they are often used for research as they are still much more readily available than genuine DCs.
Mo-DC or MDDC refers to cells matured from monocytes.
Dendritic
cells are derived from hematopoietic bone marrow progenitor cells.
These progenitor cells initially transform into immature dendritic
cells. These cells are characterized by high endocytic activity and low
T-cell activation potential. Immature dendritic cells constantly
sample the surrounding environment for pathogens such as viruses and bacteria. This is done through pattern recognition receptors (PRRs) such as the toll-like receptors (TLRs). TLRs recognize specific chemical signatures found on subsets of pathogens. Immature dendritic cells may also phagocytose
small quantities of membrane from live own cells, in a process called
nibbling. Once they have come into contact with a presentable antigen,
they become activated into mature dendritic cells and begin to migrate
to a lymph node. Immature dendritic cells phagocytose pathogens and degrade their proteins into small pieces and upon maturation present those fragments at their cell surface using MHC molecules. Simultaneously, they upregulate cell-surface receptors that act as co-receptors in T-cell activation such as CD80 (B7.1), CD86 (B7.2), and CD40 greatly enhancing their ability to activate T-cells. They also upregulate CCR7, a chemotactic receptor that induces the dendritic cell to travel through the blood stream to the spleen or through the lymphatic system to a lymph node. Here they act as antigen-presenting cells: they activate helper T-cells and killer T-cells as well as B-cells
by presenting them with antigens derived from the pathogen, alongside
non-antigen specific costimulatory signals. Dendritic cells can also
induce T-cell tolerance (unresponsiveness). Certain C-type lectin
receptors (CLRs) on the surface of dendritic cells, some functioning as
PRRs, help instruct dendritic cells as to when it is appropriate to
induce immune tolerance rather than lymphocyte activation.
Every helper T-cell is specific to one particular antigen. Only professional antigen-presenting cells
(macrophages, B lymphocytes, and dendritic cells) are able to activate a
resting helper T-cell when the matching antigen is presented. However,
in non-lymphoid organs, macrophages and B cells can only activate memory T cells whereas dendritic cells can activate both memory and naive T cells,
and are the most potent of all the antigen-presenting cells. In the
lymph node and secondary lymphoid organs, all three cell types can
activate naive T cells. Whereas mature dendritic cells are able to
activate antigen-specific naive CD8+ T cells, the formation of CD8+ memory T cells requires the interaction of dendritic cells with CD4+helper T cells. This help from CD4+ T cells additionally activates the matured dendritic cells and licenses them to efficiently induce CD8+ memory T cells, which are also able to be expanded a second time. For this activation of dendritic cells, concurrent interaction of all three cell types, namely CD4+ T helper cells, CD8+ T cells and dendritic cells, seems to be required.
As mentioned above, mDC probably arise from monocytes, white blood cells which circulate in the body and, depending on the right signal, can turn into either dendritic cells or macrophages. The monocytes in turn are formed from stem cells in the bone marrow.
Monocyte-derived dendritic cells can be generated in vitro from peripheral blood mononuclear cell
(PBMCs). Plating of PBMCs in a tissue culture flask permits adherence
of monocytes. Treatment of these monocytes with interleukin 4 (IL-4) and
granulocyte-macrophage colony stimulating factor (GM-CSF) leads to
differentiation to immature dendritic cells (iDCs) in about a week.
Subsequent treatment with tumor necrosis factor (TNF) further
differentiates the iDCs into mature dendritic cells. Monocytes can be
induced to differentiate into dendritic cells by a self-peptide Ep1.B
derived from apolipoprotein E. These are primarily tolerogenic plasmacytoid dendritic cells.
Life span
In
mice, it has been estimated that dendritic cells are replenished from
the blood at a rate of 4000 cells per hour, and undergo a limited number
of divisions during their residence in the spleen over 10 to 14 days.
Research challenges
The
exact genesis and development of the different types and subsets of
dendritic cells and their interrelationship is only marginally
understood at the moment, as dendritic cells are so rare and difficult
to isolate that only in recent years they have become subject of focused
research. Distinct surface antigens that characterize dendritic cells
have only become known from 2000 on; before that, researchers had to
work with a 'cocktail' of several antigens which, used in combination,
result in isolation of cells with characteristics unique to DCs.
Cytokines
The
dendritic cells are constantly in communication with other cells in the
body. This communication can take the form of direct cell–cell contact
based on the interaction of cell-surface proteins. An example of this
includes the interaction of the membrane proteins of the B7 family of the dendritic cell with CD28 present on the lymphocyte. However, the cell–cell interaction can also take place at a distance via cytokines.
For example, stimulating dendritic cells in vivo with microbial extracts causes the dendritic cells to rapidly begin producing IL-12. IL-12 is a signal that helps send naive CD4 T cells towards a Th1
phenotype. The ultimate consequence is priming and activation of the
immune system for attack against the antigens which the dendritic cell
presents on its surface. However, there are differences in the cytokines
produced depending on the type of dendritic cell. The plasmacytoid DC
has the ability to produce huge amounts of type-1 IFNs, which recruit more activated macrophages to allow phagocytosis.
Disease
Blastic plasmacytoid dendritic cell neoplasm
Blastic plasmacytoid dendritic cell neoplasm is a rare type of myeloid
cancer in which malignant pDCs infiltrate the skin, bone marrow,
central nervous system, and other tissues. Typically, the disease
presents with skin lesions (e.g. nodules, tumors, papules, bruise-like patches, and/or ulcers) that most often occur on the head, face, and upper torso. This presentation may be accompanied by cPC infiltrations into other tissues to result in swollen lymph nodes, enlarged liver, enlarged spleen, symptoms of central nervous system
dysfunction, and similar abnormalities in breasts, eyes, kidneys,
lungs, gastrointestinal tract, bone, sinuses, ears, and/or testes. The disease may also present as a pDC leukemia, i.e. increased levels of malignant pDC in blood (i.e. >2% of nucleated cells) and bone marrow and evidence (i.e. cytopenias) of bone marrow failure. Blastic plasmacytoid dendritic cell neoplasm has a high rate of recurrence following initial treatments with various chemotherapy regimens. In consequence, the disease has a poor overall prognosis and newer chemotherapeutic and novel non-chemotherapeutic drug regimens to improve the situation are under study.
Viral infection
HIV, which causes AIDS, can bind to dendritic cells via various receptors expressed on the cell. The best studied example is DC-SIGN
(usually on MDC subset 1, but also on other subsets under certain
conditions; since not all dendritic cell subsets express DC-SIGN, its
exact role in sexual HIV-1 transmission is not clear). When the dendritic cell takes up HIV and then travels to the lymph node, the virus can be transferred to helper CD4+ T-cells,
contributing to the developing infection. This infection of dendritic
cells by HIV explains one mechanism by which the virus could persist
after prolonged HAART.
Many other viruses, such as the SARS virus, seem to use DC-SIGN to 'hitchhike' to its target cells.
However, most work with virus binding to DC-SIGN expressing cells has
been conducted using in vitro derived cells such as moDCs. The
physiological role of DC-SIGN in vivo is more difficult to ascertain.
Cancer
Dendritic
cells are usually not abundant at tumor sites, but increased densities
of populations of dendritic cells have been associated with better
clinical outcome, suggesting that these cells can participate in
controlling cancer progression.
Lung cancers have been found to include four different subsets of
dendritic cells: three classical dendritic cell subsets and one
plasmacytoid dendritic cell subset. At least some of these dendritic cell subsets can activate CD4+ helper T cells and CD8+ cytotoxic T cells, which are immune cells that can also suppress tumor
growth. In experimental models, dendritic cells have also been shown to
contribute to the success of cancer immunotherapies, for example with
the immune checkpoint blocker anti-PD-1.
The
above applies to humans. In other organisms, the function of dendritic
cells can differ slightly. However, the principal function of dendritic
cells as known to date is always to act as an immune sentinel. They
survey the body and collect information relevant to the immune system,
they are then able to instruct and direct the adaptive arms to respond
to challenges.
In addition, an immediate precursor to myeloid and lymphoid dendritic cells of the spleen has been identified.
This precursor, termed pre-DC, lacks MHC class II surface expression,
and is distinct from monocytes, which primarily give rise to DCs in
non-lymphoid tissues.
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. There are at least 80 types of autoimmune diseases. Nearly any body part can be involved. Common symptoms include low grade fever and feeling tired. Often symptoms come and go.
About 24 million (7%) people in the United States are affected by an autoimmune disease. Women are more commonly affected than men. Often they start during adulthood. The first autoimmune diseases were described in the early 1900s.
Signs and symptoms
Rheumatoid arthritis
Autoimmune diseases present similar symptoms across the more than eighty different types.
The appearance and severity of these signs and symptoms depends on the
location and type of autoimmune response that occurs. An individual may
also have more than one autoimmune disease simultaneously, and display
symptoms of multiple diseases. Signs and symptoms presented, and the
disease itself, can be influenced by various other factors such as age,
hormones, and environmental factors. In general, the common symptoms are:
Fatigue
Low grade fever
General feeling of unwell (malaise)
Muscle aches and joint pain
Rash on different areas of the skin
The appearance of these signs and symptoms can fluctuate, and when they reappear, it is known as a flare-up. Such signs and symptoms may aid in diagnosis by supporting the results from biologic markers of autoimmune diseases.
There are several areas that are commonly impacted by autoimmune
diseases. These areas include: blood vessels, underlying connective
tissues, joints and muscles, red blood cells, skin, and endocrine glands
(such as thyroid or pancreas glands).
These diseases tend to have characteristic pathological effects
that characterize them as an autoimmune disease. Such features include
damage to or destruction of tissues where there is an abnormal immune
response, altered organ growth, and altered organ function depending on
the location of the disease.
Some diseases are organ specific and are restricted to affecting
certain tissues, while others are systemic diseases that impact many
tissues throughout the body. Signs and symptoms may vary depending on
which of these categories an individual’s disease falls under.
Cancer
Research
suggests an overall correlation between autoimmune diseases and cancer,
in that having an autoimmune disease increases the risk or likelihood of
developing certain cancers. Autoimmune diseases cause inflammation through a variety of mechanisms, however, the way in which inflammation is created does not greatly influence cancer risk. Rather, the cancer risk is largely dependent on the fact that all autoimmune diseases increase chronic inflammation which has been linked to cancer. Below are some autoimmune diseases most commonly linked to cancer including celiac disease, inflammatory bowel disease (Crohn's disease and ulcerative colitis), multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.
Examples
Coeliac Disease
Coeliac disease presents the strongest associations to gastrointestinal and lymphoproliferative cancers. In coeliac disease, the autoimmune reaction is caused by the body’s loss of immune tolerance to ingested gluten, found primarily in wheat, barley, and rye.
This explains the increased risk of gastrointestinal cancers, as the
gastrointestinal tract includes the esophagus, stomach, small intestine,
large intestine, rectum, and anus, all areas that the ingested gluten
would traverse in digestion. The incidence of gastrointestinal cancer can be partially reduced or eliminated if a patient removes gluten from their diet. Additionally, celiac disease is correlated with lymphoproliferative cancers.
Inflammatory Bowel Disease
Inflammatory bowel disease is associated with cancers of the gastrointestinal tract and some lymphoproliferative cancers. Inflammatory bowel disease (IBD) can be further categorized as Crohn's disease or ulcerative colitis. In both cases, individuals with IBD lose immune tolerance for normal bacteria present in the gut microbiome. In this case, the immune system attacks the bacteria and induces chronic inflammation, which has been linked to increased cancer risk.
Multiple Sclerosis
Multiple sclerosis is associated with decreased risk of cancer overall but an increased risk of central nervous system cancer, primarily in the brain. Multiple sclerosis is a neurodegenerative disease in which T-cells – a specific type of immune cells – attack the important myelin sheath in brain neurons. This reduces the nervous system function, creating inflammation and subsequent cancer of the brain.
Rheumatoid Arthritis
Rheumatoid arthritis presents mild, yet significant associations with focal cancers all throughout the body as well as lymphoproliferative cancers. In rheumatoid arthritis, cells that make up the body’s joints and cartilages become invasive and induce local inflammation.
Additionally, the chronic inflammation and over-activation of the
immune system creates an environment that favors further malignant
transformation of other cells. This can explain the associations to
cancer of the lungs and skin as well as the increased risk of other
hematologic cancers none of which are directly affected by the
inflammation of joints.
Systemic Lupus Erythematosus
Systemic lupus erythematosus is associated with focal cancers throughout the body and lymphoproliferative cancers. Systemic lupus erythematosus affects multiple organ systems and is characterized by a widespread loss of immune tolerance. The chronic inflammation
throughout the entire body promotes the malignant transformation of
other cells which contributes to the increased risk of systemic and
lymphoproliferative cancers.
Conversely, systemic lupus erythematosus is correlated with a decrease
in some cancers. This is best explained by increased immunosurveillance
in these areas, however, the mechanism for why these areas experience
lower incidence is poorly understood.
Aplastic anemia
In aplastic anemia
the body fails to produce blood cells in sufficient numbers. Blood
cells are produced in the bone marrow by stem cells that reside there.
Aplastic anaemia causes a deficiency of all blood cell types: red blood
cells, white blood cells, and platelets.
Autoimmune
diseases are conditions in which the human immune system attacks
healthy human tissues within the body. The exact genes responsible for
causing each autoimmune disease have not been found. However, several
experimental methods such as the genome-wide association scans have been
used to identify certain genetic risk variants that may or may not be
responsible.
Research focusing on both genome scanning and family trait inheritance
analysis has enabled scientists to further understand the etiology of
autoimmune diseases such as Type 1 diabetes and Rheumatoid arthritis.
Type 1 diabetes is a condition in which pancreatic β-cells are targeted and destroyed by the immune system.
The condition is a result of neo-natal mutations to the insulin gene
(INS) which is responsible for mediating the production of the insulin
in the pancreas.
The INS gene is located on the short arm of chromosome 11p15.5 in
between the genes for tyrosine hydroxylase and insulin-like growth
factor II.
In addition to chromosome 11, a genetic determinant of type 1 diabetes
is a locus called the major histocompatibility complex (MHC) located on
chromosome 6p21.
Rheumatoid arthritis: Although there is no complete genetic mapping
for this condition, several genes are thought to play a role in causing
RA. The genes that influence the human immune system contain a TNF
receptor associated factor 1(TRAF1). This TRAF1 is located on chromosome
9q33-34.
In addition, B1 genes in the human genome contain an increased
concentration of HLA-DRB1 alleles that are most commonly seen in RA
patients. RA can vary in severity as a consequence of polymorphisms within the genome.
Environmental factors
A
range of environmental factors have been recognized as either having a
direct role in development, or being a catalyst to many autoimmune
diseases. Current studies "indicate" up to seventy percent of autoimmune
disease are perhaps due to environmental factors, including: chemicals,
infection, diet, and gut dysbiosis. A single set of steps has been
identified to be the most likely theory for autoimmune disease onset
still there is of yet no definitive proof.
Environmental triggers
Reduced oral tolerance
Gut dysbiosis
Enhanced gut permeability
Increased immune reactivity
Autoimmunity
Chemicals can be found within the direct environment or in the form
of drugs, including: hydrazines, hair dyes, trichloroethylene,
tartrazines, hazardous wastes, and industrial emissions.
UV radiation is found to be a possible cause of development of the autoimmune disease dermatomyositis, exposure to pesticides plays a role in rheumatoid arthritis development, and vitamin D has been found to be a key in preventing immune dysfunctions in older populations.
Infectious agents are considered T cell activators, a step needed for
activation of autoimmune diseases. These mechanisms are relatively
unknown, but are one of the current alternative theories to explain
autoimmune diseases triggered by infection such as Guillain-Barre
syndrome and rheumatic fever.
Pathophysiology
The human immune system typically produces both T cells and B cells that are capable of being reactive with self-protein,
but these self-reactive cells are usually either killed prior to
becoming active within the immune system, placed into a state of anergy
(silently removed from their role within the immune system due to
over-activation), or removed from their role within the immune system by
regulatory cells. When any one of these mechanisms fail, it is possible
to have a reservoir of self-reactive cells that become functional
within the immune system. The mechanisms of preventing self-reactive T
cells from being created take place through negative selection process
within the thymus as the T cell is developing into a mature immune cell.
Some infections, such as Campylobacter jejuni, have antigens that are similar (but not identical) to our own self-molecules. In this case, a normal immune response to C. jejuni
can result in the production of antibodies that also react to a lesser
degree with gangliosides of myelin sheath surrounding peripheral nerves'
axons (i.e., Guillain–Barré).
A major understanding of the underlying pathophysiology of autoimmune
diseases has been the application of genome-wide association scans that
have identified a degree of genetic sharing among the autoimmune
diseases.
Autoimmunity,
on the other hand, is the presence of self-reactive immune response
(e.g., auto-antibodies, self-reactive T cells), with or without damage
or pathology resulting from it. This may be restricted to certain organs (e.g. in autoimmune thyroiditis) or involve a particular tissue in different places (e.g. Goodpasture's disease which may affect the basement membrane in both the lung and the kidney).
There are so many different theories as to how an autoimmune disease state arises. Some common ones are listed below.
Diagnosis
For a disease to be regarded as an autoimmune disease it needs to answer to Witebsky's postulates (first formulated by Ernest Witebsky and colleagues in 1957 and modified in 1994):
Indirect evidence based on reproduction of the autoimmune disease in experimental animals
Circumstantial evidence from clinical clues
Symptoms of early autoimmune disease are often the exact same as
common illnesses, including: fatigue, fever, malaise, joint pain, and
rash. Due to the fact symptoms vary for affected location, disease
causing agents, and individuals, it is difficult for proper diagnosis.
Typically, diagnosis begins with looking into a patient’s family's
history for genetic predisposition. This is combined with various tests,
as no single test can identify an autoimmune disease.
Antinuclear antibody
A test used to identify abnormal proteins, known as antinuclear antibodies, produced when the body attacks its own tissues.
It may test positive in several disorders. This test is most useful for
diagnosing systemic lupus erythematosus, having a 95% positive test
rate.
Complete blood count
A test taking measurements on maturity levels, count, and size of blood cells.
Targeted cells include: red blood cells, white blood cells, hemoglobin,
hematocrit, and platelets. Based on increased or decreased numbers in
these counts, underlying medical conditions may be present; typically,
autoimmune disease is represented by low white blood cell count
(Leukopenia). For proper diagnosis, further testing is needed.
Complement
A
test used to measure levels of a protein group of the immune system
called complement within blood. If complement is found in low levels,
this may be an indication of disease.
C reactive protein
C reactive protein, a protein made in the liver generally increases with inflammation, and may be high in autoimmune disease.
Erythrocyte sedimentation rate
This
test measures the rate at which a patient’s blood cells descend in a
test tube. More rapid descents may indicate inflammation, a common
symptom of autoimmune disease.
If these tests are indicative antibody abnormalities and
inflammation, further tests will be conducted to identify the autoimmune
disease present.
Treatment
Treatment
depends on the type and severity of the condition. The majority of the
autoimmune diseases are chronic and there is no definitive cure, but
symptoms can be alleviated and controlled with treatment.
Overall, the aim of the various treatment methods is to lessen the
presented symptoms for relief and manipulate the body’s autoimmune
response, while still preserving the ability of the patient to combat
diseases that they may encounter. Traditional treatment options may include immunosuppressant drugs to weaken the overall immune response, such as:
Non-steroidal anti-inflammatory drugs (NSAIDs) to reduce inflammation
Glucocorticoids to reduce inflammation
Disease-modifying anti-rheumatic drugs (DMARDs) to decrease the
damaging tissue and organ effects of the inflammatory autoimmune
response
Other standard treatment methods include:
Vitamin or hormone supplements for what the body is lacking due to the disease (insulin, vitamin B12, thyroid hormone, etc.)
Blood transfusions if the disease is blood related
Physical therapy if the disease impacts bones, joints, or muscles
Because these drugs aim to reduce the immune response against the
body’s own tissues, there are side effects of these traditional
treatment methods, such as being more vulnerable to infections that can
potentially be life threatening. There are new advancements in medicine
for the treatment of autoimmune diseases that are currently being
researched, developed, and used today, especially when traditional
treatment options fail. These methods aim to either block the activation
of pathogenic cells in the body, or alter the pathway that suppresses
these cells naturally.
The goal for these advancements is to have treatment options available
that are less toxic to the patient, and have more specific targets. Such options include:
Monoclonal antibodies that can be used to block pro-inflammatory cytokines
Antigen-specific immunotherapy which allows immune cells to specifically target the abnormal cells that cause autoimmune disease
Co-stimulatory blockade that works to block the pathway that leads to the autoimmune response
Regulatory T cell therapy that utilizes this special type of T cell to suppress the autoimmune response
Epidemiology
The
first estimate of US prevalence for autoimmune diseases as a group was
published in 1997 by Jacobson, et al. They reported US prevalence to be
around 9 million, applying prevalence estimates for 24 diseases to a US
population of 279 million. Jacobson's work was updated by Hayter & Cook in 2012. This study used Witebsky's postulates, as revised by Rose & Bona,
to extend the list to 81 diseases and estimated overall cumulative US
prevalence for the 81 autoimmune diseases at 5.0%, with 3.0% for males
and 7.1% for females. The estimated community
prevalence, which takes into account the observation that many people
have more than one autoimmune disease, was 4.5% overall, with 2.7% for
males and 6.4% for females.
National Health and Nutrition Examination Surveys conducted in the US
from the 1980s to present day, have shown an increase of antinuclear
antibodies, a common biomarker for autoimmune diseases. This shows that
there has been an increase in the prevalence of autoimmune diseases in
recent years pointing to a stronger influence of environment factors as a
risk factor for autoimmune diseases.
Research
In
both autoimmune and inflammatory diseases, the condition arises through
aberrant reactions of the human adaptive or innate immune systems. In
autoimmunity, the patient's immune system is activated against the
body's own proteins. In chronic inflammatory diseases, neutrophils and other leukocytes are constitutively recruited by cytokines and chemokines, resulting in tissue damage.
Mitigation of inflammation by activation of anti-inflammatory
genes and the suppression of inflammatory genes in immune cells is a
promising therapeutic approach. There is a body of evidence that once the production of autoantibodies has been initialized, autoantibodies have the capacity to maintain their own production.
Stem cell transplantation is being studied and has shown promising results in certain cases.
Altered glycan theory
According to this theory, the effector function of the immune response is mediated by the glycans
(polysaccharides) displayed by the cells and humoral components of the
immune system. Individuals with autoimmunity have alterations in their
glycosylation profile such that a proinflammatory immune response is
favored. It is further hypothesized that individual autoimmune diseases
will have unique glycan signatures.
Hygiene hypothesis
According to the hygiene hypothesis,
high levels of cleanliness expose children to fewer antigens than in
the past, causing their immune systems to become overactive and more
likely to misidentify own tissues as foreign, resulting in autoimmune or
allergic conditions such as asthma.
Vitamin D Influence on Immune Response
Vitamin D is known as an immune regulator that assists in the adaptive and innate immune response.
A deficiency in Vitamin D, from hereditary or environmental influence,
can lead to a more inefficient and weaker immune response and seen as a
contributing factor to the development of autoimmune diseases.
With Vitamin D present, vitamin D response elements (VDRE) are encoded
and expressed via pattern recognition receptors (PRR) responses and the
genes associated with those responses. The specific DNA target sequence expressed is known as 1,25-(OH)2D3. The expression of 1,25-(OH)2D3 can be induced by Macrophages, Dendritic cells, T-cells, and B-cells.
In the presence of 1,25-(OH)2D3, the immune system's production of
inflammatory cytokines are suppressed and more tolerogenic regulatory
T-cells are expressed. This is due to Vitamin D's influence on cell maturation, specifically T-cells, and their phenotype expression.
Lack of 1,25-(OH)2D3 expression can lead to less tolerant regulatory
T-cells, larger presentation of antigens to less tolerant T-cells, and
increased inflammatory response.
Contemporary illustration of the 1868 Washita Massacre by the 7th Cavalry against Black Kettle's band of Cheyennes, during the American Indian Wars.
Violence and conflict with colonists were also important causes of the
decline of certain indigenous American populations since the 16th
century.
Population figures for the indigenous people of the Americas prior to colonization
have proven difficult to establish. Scholars rely on archaeological
data and written records from European settlers. By the end of the 20th
century most scholars gravitated toward an estimate of around 50
million—with some historians arguing for an estimate of 100 million or
more.
In an effort to circumvent the hold the Ottoman Empire held on the overland trade routes to East Asia and the hold that the Aeterni regis granted to Portugal on maritime routes via the African coast and the Indian Ocean, the monarchs of the nascent Spanish Empire decided to fund Columbus' voyage in 1492, which eventually led to the establishment of settler-colonial states and the migration of millions of Europeans to the Americas. The population of African and European
peoples in the Americas grew steadily starting in 1492, while at the
same time the indigenous population began to plummet. Eurasian diseases
such as influenza, pneumonic plagues, and smallpox devastated the Native Americans, who did not have immunity to them. Conflict and outright warfare
with Western European newcomers and other American tribes further
reduced populations and disrupted traditional societies. The extent and
causes of decline have been characterized as genocide.
Population overview
Natives of North America.
Natives of the South of America.
Columbus landing on Hispaniola, Dec. 6, 1492; greeted by Arawak Indians. Theodore de Bry
Given the fragmentary nature of the evidence, even semi-accurate
pre-Columbian population figures are thought impossible to obtain.
Scholars have varied widely on the estimated size of the indigenous
populations prior to colonization and on the effects of European contact. Estimates are made by extrapolations from small bits of data. In 1976, geographer William Denevan
used the existing estimates to derive a "consensus count" of about
54 million people. Nonetheless, more recent estimates still range
widely.
In 1992, Denevan suggested that the total population was approximately
53.9 million and the populations by region were, approximately, 3.8
million for the United State and Canada , 17.2 million for Mexico, 5.6
million for Central America, 3 million for the Caribbean, 15.7 million
for the Andes and 8.6 million for lowland South America.
Using an estimate of approximately 37 million people in Mexico, Central and South America in 1492 (including 6 million in the Aztec Empire, 5–10 million in the Mayan States, 11 million in what is now Brazil, and 12 million in the Inca Empire), the lowest estimates give a death toll due from disease of 80% by the end of the 17th century (nine million people in 1650).
Latin America would match its 15th-century population early in the 19th
century; it numbered 17 million in 1800, 30 million in 1850, 61 million
in 1900, 105 million in 1930, 218 million in 1960, 361 million in 1980,
and 563 million in 2005. In the last three decades of the 16th century, the population of present-day Mexico dropped to about one million people. The Maya
population is today estimated at six million, which is about the same
as at the end of the 15th century, according to some estimates.
In what is now Brazil, the indigenous population declined from a
pre-Columbian high of an estimated four million to some 300,000.
While it is difficult to determine exactly how many Natives lived in North America before Columbus, estimates range from 7 million people to a high of 18 million.
The aboriginal population of Canada during the late 15th century is estimated to have been between 500,000 and two million. Repeated outbreaks of Old World infectious diseases such as influenza, measles and smallpox
(to which they had no natural immunity) were the main cause of
depopulation. This combined with other factors such as dispossession
from European/Canadian settlements and numerous violent conflicts resulted in a forty- to eighty-percent aboriginal population decrease after contact. For example, during the late 1630s, smallpox killed over half of the Wyandot (Huron), who controlled most of the early North American fur trade in what became Canada. They were reduced to fewer than 10,000 people.
The population debate has often had ideological underpinnings. Low estimates were sometimes reflective of European notions of cultural and racial superiority. Historian Francis Jennings
argued, "Scholarly wisdom long held that Indians were so inferior in
mind and works that they could not possibly have created or sustained
large populations."
In 1998, Africanist Historian David Henige
argued many population estimates are the result of arbitrary formulas
selectively applied to numbers from unreliable historical sources. He
believes this is a weakness of several contributors to the field, and
insists there is not sufficient evidence to produce population numbers
that have any real meaning.
The indigenous population of the Americas in 1492 was not
necessarily at a high point and may actually have been in decline in
some areas. Indigenous populations in most areas of the Americas reached
a low point by the early 20th century. In most cases, populations have
since begun to climb.
Over 60 million Brazilians possess at least one Native South American ancestor, according to a mitochondrial DNA study.
Genetic diversity and population structure in the American land mass using DNA micro-satellite markers (genotype) sampled from North, Central, and South America have been analyzed against similar data available from other indigenous populations worldwide. The Amerindian populations show a lower genetic diversity than populations from other continental regions. Observed is both a decreasing genetic diversity as geographic distance from the Bering Strait occurs and a decreasing genetic similarity to Siberian populations from Alaska (genetic entry point).
Also observed is evidence of a higher level of diversity and lower
level of population structure in western South America compared to
eastern South America. A relative lack of differentiation between Mesoamerican and Andean populations is a scenario that implies coastal routes were easier than inland routes for migrating peoples (Paleo-Indians) to traverse.
The overall pattern that is emerging suggests that the Americas were
recently colonized by a small number of individuals (effective size of
about 70–250), and then they grew by a factor of 10 over 800–1,000
years. The data also show that there have been genetic exchanges between Asia, the Arctic and Greenland since the initial peopling of the Americas. A new study in early 2018 suggests that the effective population size of the original founding population of Native Americans was about 250 people.
Depopulation from disease
Sixteenth-century Aztec drawings of victims of smallpox (above) and measles (below)
Graph demonstrating the population collapse in Central Mexico brought on by successive epidemics in the early colonial period.
According to Noble David Cook, a community of scholars has recently,
albeit slowly, "been quietly accumulating piece by piece data on early
epidemics in the Americas and their relation to the subjugation of
native peoples." They now believe that widespread epidemic disease, to
which the natives had no prior exposure or resistance, was the primary
cause of the massive population decline of the Native Americans.
Earlier explanations for the population decline of the American natives
include the European immigrants' accounts of the brutal practices of
the Spanish conquistadores, as recorded by the Spaniards themselves. This was applied through the encomienda,
which was a system ostensibly set up to protect people from warring
tribes as well as to teach them the Spanish language and the Catholic religion, but in practice was tantamount to serfdom and slavery. The most notable account was that of the DominicanfriarBartolomé de las Casas, whose writings vividly depict Spanish atrocities committed in particular against the Taínos. It took five years for the Taíno rebellion to be quelled by both the Real Audiencia—through diplomatic sabotage, and through the Indian auxiliaries fighting with the Spanish. After Emperor Charles V
personally eradicated the notion of the encomienda system as a use for
slave labour, there were not enough Spanish to have caused such a large
population decline. The second European explanation was a perceived divine approval, in which God removed the natives as part of His "divine plan" to make way for a new Christian
civilization. Many Native Americans viewed their troubles in terms of
religious or supernatural causes within their own belief systems.
Soon after Europeans and enslaved Africans arrived in the New
World, bringing with them the infectious diseases of Europe and Africa,
observers noted immense numbers of indigenous Americans began to die
from these diseases. One reason this death toll was overlooked is that
once introduced, the diseases raced ahead of European immigration in
many areas. The disease killed a sizable portion of the populations
before European written records were made. After the epidemics had
already killed massive numbers of natives, many newer European
immigrants assumed that there had always been relatively few indigenous
peoples. The scope of the epidemics over the years was tremendous,
killing millions of people—possibly in excess of 90% of the population
in the hardest-hit areas—and creating one of "the greatest human
catastrophe in history, far exceeding even the disaster of the Black Death of medieval Europe", which had killed up to one-third of the people in Europe and Asia between 1347 and 1351.
This transfer of disease between the Old and New Worlds was later studied as part of what has been labeled the "Columbian Exchange".
The epidemics had very different effects in different regions of
the Americas. The most vulnerable groups were those with a relatively
small population and few built-up immunities. Many island-based groups
were annihilated. The Caribs and Arawaks of the Caribbean nearly ceased to exist, as did the Beothuks of Newfoundland. While disease raged swiftly through the densely populated empires of Mesoamerica, the more scattered populations of North America saw a slower spread.
The European colonization of the Americas resulted in the deaths of so many people it contributed to climatic change and temporary global cooling, according to scientists from University College London. A century after the arrival of Christopher Columbus, some 90% of indigenous Americans had perished from "wave after wave of disease", along with mass slavery and war, in what researchers have described as the "great dying".
According to one of the researchers, UCL Geography Professor Mark
Maslin, the large death toll also boosted the economies of Europe: "the
depopulation of the Americas may have inadvertently allowed the
Europeans to dominate the world. It also allowed for the Industrial
Revolution and for Europeans to continue that domination."
Historian Andrés Reséndez of University of California, Davis
asserts that evidence suggests "slavery has emerged as a major killer"
of the indigenous populations of the Caribbean between 1492 and 1550
rather than diseases such as smallpox, influenza and malaria. He posits that unlike the populations of Europe who rebounded following the Black Death,
no such rebound occurred for the indigenous populations of the
Americas. He concludes that, even though the Spanish were aware of
deadly diseases such as smallpox, there is no mention of them in the New
World until 1519, meaning perhaps they didn't spread as fast as
initially believed, and that unlike Europeans, the indigenous
populations were subjected to brutal forced labor in gold and silver
mines on a massive scale. Anthropologist Jason Hickel estimates that a third of Arawak workers died every six months from lethal forced labor in these mines.
Similarly, historian Jeffrey Ostler at The University of Oregon
has argued that population collapses in the Americas throughout
colonization were not mainly due to lack of Native immunity to European
disease. Instead, he claims that "When severe epidemics did hit, it was
often less because Native bodies lacked immunity than because European
colonialism disrupted Native communities and damaged their resources,
making them more vulnerable to pathogens." In specific regards to Spanish colonization
of northern Florida and southeastern Georgia, Native peoples there
"were subject to forced labor and, because of poor living conditions and
malnutrition, succumbed to wave after wave of unidentifiable diseases."
Further, in relation to British colonization in the Northeast, Algonquian speaking tribes
in Virginia and Maryland "suffered from a variety of diseases,
including malaria, typhus, and possibly smallpox." These diseases were
not solely a case of Native susceptibility, however, because "as
colonists took their resources, Native communities were subject to
malnutrition, starvation, and social stress, all making people more
vulnerable to pathogens. Repeated epidemics created additional trauma
and population loss, which in turn disrupted the provision of
healthcare." Such conditions would continue, alongside rampant disease
in Native communities, throughout colonization, the formation of the
United States, and multiple forced removals, as Ostler explains that
many scholars "have yet to come to grips with how U.S. expansion created
conditions that made Native communities acutely vulnerable to pathogens
and how severely disease impacted them. ... Historians continue to
ignore the catastrophic impact of disease and its relationship to U.S.
policy and action even when it is right before their eyes."
Historian David Stannard
says that by "focusing almost entirely on disease ... contemporary
authors increasingly have created the impression that the eradication of
those tens of millions of people was inadvertent—a sad, but both
inevitable and "unintended consequence" of human migration and
progress," and asserts that their destruction "was neither inadvertent
nor inevitable," but the result of microbial pestilence and purposeful
genocide working in tandem.
Virulence and mortality
Photograph from 1892 of a pile of American bison skulls in Detroit (MI) waiting to be ground for fertilizer or charcoal.
Viral and bacterial
diseases that kill victims before the illnesses spread to others tend
to flare up and then die out. A more resilient disease would establish
an equilibrium; if its victims lived beyond infection,
the disease would spread further. A similar evolutionary pressure acts
upon victim populations, as those lacking genetic resistance to common
diseases die and do not leave descendants, whereas those who are
resistant procreate and pass resistant genes to their offspring. For
example, in the first fifty years of the sixteenth century, an unusually
strong strain of syphilis
killed a high proportion of infected Europeans within a few months;
over time, however, the disease has become much less virulent.
"Rath & Wright's buffalo hide yard in 1878, showing 40,000 buffalo hides, Dodge City, Kansas."
Thus both infectious diseases and populations tend to evolve towards
an equilibrium in which the common diseases are non-symptomatic, mild or
manageably chronic.
When a population that has been relatively isolated is exposed to new
diseases, it has no resistance to the new diseases (the population is
"immunologically naive"). These people die at a much higher rate,
resulting in what is known as a "virgin soil" epidemic.
Before the European arrival, the Americas had been isolated from the
Eurasian-African landmass. The peoples of the Old World had had
thousands of years for their populations to accommodate to their common
diseases.
The fact that all members of an immunologically naive population
are exposed to a new disease simultaneously increases the fatalities. In
populations where the disease is endemic, generations of individuals
acquired immunity; most adults had exposure to the disease at a young
age. Because they were resistant to reinfection, they are able to care
for individuals who caught the disease for the first time, including the
next generation of children. With proper care, many of these "childhood diseases"
are often survivable. In a naive population, all age groups are
affected at once, leaving few or no healthy caregivers to nurse the
sick. With no resistant individuals healthy enough to tend to the ill, a
disease may have higher fatalities.
The natives of the Americas were faced with several new diseases
at once creating a situation where some who successfully resisted one
disease might die from another. Multiple simultaneous infections (e.g.,
smallpox and typhus at the same time) or in close succession (e.g.,
smallpox in an individual who was still weak from a recent bout of
typhus) are more deadly than just the sum of the individual diseases. In
this scenario, death rates can also be elevated by combinations of new
and familiar diseases: smallpox in combination with American strains of yaws, for example.
Other contributing factors:
Native American medical treatments such as sweat baths and cold water immersion (practiced in some areas) weakened some patients and probably increased mortality rates.
Europeans brought many diseases with them because they had many more domesticated animals than the Native Americans. Domestication
usually means close and frequent contact between animals and people,
which allows diseases of domestic animals to migrate into the human
population when the necessary mutations occur.
The Eurasian landmass extends many thousands of miles along an
east–west axis. Climate zones also extend for thousands of miles, which
facilitated the spread of agriculture, domestication of animals, and the
diseases associated with domestication. The Americas extend mainly
north and south, which, according to the environmental determinist
theory popularized by Jared Diamond in Guns, Germs, and Steel, meant that it was much harder for cultivated plant species, domesticated animals, and diseases to migrate.
Biological warfare
Tupac Amaru II in the National Museum of Archeology, Anthropology and History of Peru.
When Old World diseases were first carried to the Americas at the end
of the fifteenth century, they spread throughout the southern and
northern hemispheres, leaving the indigenous populations in near ruins.
No evidence has been discovered that the earliest Spanish colonists and
missionaries deliberately attempted to infect the American natives, and
some effort was actually made to limit the devastating effects of
disease before it killed off what remained of their forced slave labor
under their encomienda system.
The cattle introduced by the Spanish contaminated various water
reserves which Native Americans dug in the fields to accumulate
rainwater. In response, the Franciscans and Dominicans created public fountains and aqueducts to guarantee access to drinking water. But when the Franciscans lost their privileges in 1572, many of these fountains were no longer guarded and so deliberate well poisoning may have happened.
Although no proof of such poisoning has been found, some historians
believe the decrease of the population correlates with the end of
religious orders' control of the water.
In the centuries that followed, accusations and discussions of
biological warfare were common. Well-documented accounts of incidents
involving both threats and acts of deliberate infection are very rare,
but may have occurred more frequently than scholars have previously
acknowledged.
Many of the instances likely went unreported, and it is possible that
documents relating to such acts were deliberately destroyed, or sanitized.
By the middle of the 18th century, colonists had the knowledge and
technology to attempt biological warfare with the smallpox virus. They
well understood the concept of quarantine, and that contact with the
sick could infect the healthy with smallpox, and those who survived the
illness would not be infected again. Whether the threats were carried
out, or how effective individual attempts were, is uncertain.
One such threat was delivered by fur trader James McDougall,
who is quoted as saying to a gathering of local chiefs, "You know the
smallpox. Listen: I am the smallpox chief. In this bottle I have it
confined. All I have to do is to pull the cork, send it forth among you,
and you are dead men. But this is for my enemies and not my friends." Likewise, another fur trader threatened Pawnee Indians that if they didn't agree to certain conditions, "he would let the smallpox out of a bottle and destroy them." The Reverend Isaac McCoy was quoted in his History of Baptist Indian Missions
as saying that the white men had deliberately spread smallpox among the
Indians of the southwest, including the Pawnee tribe, and the havoc it
made was reported to General Clark and the Secretary of War. Artist and writer George Catlin
observed that Native Americans were also suspicious of vaccination,
"They see white men urging the operation so earnestly they decide that
it must be some new mode or trick of the pale face by which they hope to
gain some new advantage over them." So great was the distrust of the settlers that the Mandan chief Four Bears denounced the white man, whom he had previously treated as brothers, for deliberately bringing the disease to his people.
During the Seven Years' War, British militia took blankets from their smallpox hospital and gave them as gifts to two neutral Lenape
Indian dignitaries during a peace settlement negotiation, according to
the entry in the Captain's ledger, "To convey the Smallpox to the
Indians".
In the following weeks, the high commander of the British forces in
North America conspired with his Colonel to "Extirpate this Execreble
Race" of Native Americans, writing, "Could it not be contrived to send
the small pox among the disaffected tribes of Indians? We must on this
occasion use every stratagem in our power to reduce them." His Colonel
agreed to try. Most scholars have asserted that the 1837 Great Plains smallpox epidemic was "started among the tribes of the upper Missouri River by failure to quarantine steamboats on the river", and Captain Pratt of the St. Peter
"was guilty of contributing to the deaths of thousands of innocent
people. The law calls his offense criminal negligence. Yet in light of
all the deaths, the almost complete annihilation of the Mandans, and the
terrible suffering the region endured, the label criminal negligence is
benign, hardly befitting an action that had such horrendous
consequences."
However, some sources attribute the 1836–40 epidemic to the deliberate
communication of smallpox to Native Americans, with historian Ann F.
Ramenofsky writing, "Variola Major can be transmitted through
contaminated articles such as clothing or blankets. In the nineteenth
century, the U. S. Army sent contaminated blankets to Native Americans,
especially Plains groups, to control the Indian problem."
Well into the 20th century, deliberate infection attacks continued as
Brazilian settlers and miners transported infections intentionally to
the native groups whose lands they coveted."
Vaccination
After Edward Jenner's 1796 demonstration that the smallpox vaccination
worked, the technique became better known and smallpox became less
deadly in the United States and elsewhere. Many colonists and natives
were vaccinated, although, in some cases, officials tried to vaccinate
natives only to discover that the disease was too widespread to stop. At
other times, trade demands led to broken quarantines. In other cases,
natives refused vaccination because of suspicion of whites. The first
international healthcare expedition in history was the Balmis expedition which had the aim of vaccinating indigenous peoples against smallpox all along the Spanish Empire in 1803. In 1831, government officials vaccinated the Yankton Sioux at Sioux Agency. The Santee Sioux refused vaccination and many died.
Depopulation from European Conquest
War and violence
An 1899 chromolithograph of U.S. cavalry pursuing American Indians, artist unknown.
Storming of the Teocalli by Cortez and His Troops by Emanuel Leutze
An 1899 chromolithograph from the Werner Company of Akron, Ohio entitled Custer Massacre at Big Horn, Montana – June 25, 1876.
While epidemic disease was a leading factor of the population decline
of the American indigenous peoples after 1492, there were other
contributing factors, all of them related to European contact and
colonization. One of these factors was warfare. According to demographer
Russell Thornton, although many lives were lost in wars over the
centuries, and war sometimes contributed to the near extinction of
certain tribes, warfare and death by other violent means was a
comparatively minor cause of overall native population decline.
From the U.S. Bureau of the Census in 1894: "The Indian wars
under the government of the United States have been more than 40 in
number [Over the previous 100 years]. They have cost the lives of about
19,000 white men, women and children, including those killed in
individual combats, and the lives of about 30,000 Indians. The actual
number of killed and wounded Indians must be very much higher than the
given... Fifty percent additional would be a safe estimate..."
There is some disagreement among scholars about how widespread warfare was in pre-Columbian America, but there is general agreement that war became deadlier after the arrival of the Europeans and their firearms. The South or Central American infrastructure allowed for thousands of European conquistadors and tens of thousands of their Indian auxiliaries to attack the dominant indigenous civilization. Empires such as the Incas
depended on a highly centralized administration for the distribution of
resources. Disruption caused by the war and the colonization hampered
the traditional economy, and possibly led to shortages of food and
materials.
Across the western hemisphere, war with various Native American
civilizations constituted alliances based out of both necessity or
economic prosperity and, resulted in mass-scale intertribal warfare.
European colonization in the North American continent also contributed
to a number of wars between Native Americans, who fought over which of
them should have first access to new technology and weaponry—like in the
Beaver Wars.
Some Spaniards objected to the encomienda system, notably Bartolomé de las Casas, who insisted that the Indians were humans with souls and rights. Due to many revolts and military encounters, Emperor Charles V
helped relieve the strain on both the Indian laborers and the Spanish
vanguards probing the Caribana for military and diplomatic purposes. Later on New Laws
were promulgated in Spain in 1542 to protect isolated natives, but the
abuses in the Americas were never entirely or permanently abolished. The
Spanish also employed the pre-Columbian draft system called the mita, and treated their subjects as something between slaves and serfs.
Serfs stayed to work the land; slaves were exported to the mines, where
large numbers of them died. In other areas the Spaniards replaced the
ruling Aztecs and Incas and divided the conquered lands among themselves
ruling as the new feudal lords with often, but unsuccessful lobbying to the viceroys of the Spanish crown to pay Tlaxcalan war demnities. The infamous Bandeirantes from São Paulo, adventurers mostly of mixed Portuguese and native ancestry, penetrated steadily westward in their search for Indian slaves. Serfdom existed as such in parts of Latin America well into the 19th century, past independence. Historian Andrés Reséndez
argues that even though the Spanish were aware of the spread of
smallpox, they made no mention of it until 1519, a quarter century after
Columbus arrived in Hispaniola.
Instead he contends that enslavement in gold and silver mines was the
primary reason why the Native American population of Hispaniola dropped
so significantly. and that even though disease was a factor, the native population would have rebounded the same way Europeans did following the Black Death if it were not for the constant enslavement they were subject to. He further contends that enslavement of Native Americans was in fact the primary cause of their depopulation in Spanish territories;
that the majority of Indians enslaved were women and children compared
to the enslavement of Africans which mostly targeted adult males and in
turn they were sold at a 50% to 60% higher price, and that 2,462,000 to 4,985,000 Amerindians where enslaved between Columbus's arrival and 1900.
Friar Bartolomé de las Casas
and other dissenting Spaniards from the colonial period described the
manner in which the natives were treated by colonials. This has helped
to create an image of the Spanish conquistadores as cruel in the
extreme.
Great revenues were drawn from Hispaniola so the advent of losing manpower didn't benefit the Spanish crown. At best, the reinforcement of vanguards sent by the Council of the Indies
to explore the Caribana country and gather information on alliances or
hostilities was the main goal of the local viceroys and their adelantados. Although mass killings and atrocities
were not a significant factor in native depopulation, no mainstream
scholar dismisses the sometimes humiliating circumstances now believed
to be precipitated by civil disorder as well as Spanish cruelty.
While some California tribes were settled on reservations, others were hunted down and massacred
by 19th century American settlers. It is estimated that at least 9,400
to 16,000 California Indians were killed by non-Indians, mostly
occurring in more than 370 massacres (defined as the "intentional
killing of five or more disarmed combatants or largely unarmed
noncombatants, including women, children, and prisoners, whether in the
context of a battle or otherwise").
The populations of many Native American peoples were reduced by the common practice of intermarrying with Europeans.
Although many Indian cultures that once thrived are extinct today,
their descendants exist today in some of the bloodlines of the current
inhabitants of the Americas.
Later apologies from government officials
On 8 September 2000, the head of the United States Bureau of Indian Affairs (BIA) formally apologized for the agency's participation in the "ethnic cleansing" of Western tribes.
In a speech before representatives of Native American peoples in June, 2019, California governor Gavin Newsom apologized for the "California Genocide."
Newsom said, "That’s what it was, a genocide. No other way to describe
it. And that’s the way it needs to be described in the history books."
