Autoimmune disesse Flashcards
three requirements
should be met before a disorder is categorized as truly caused
by autoimmunity
(1) the presence of an immune reaction
specific for some self antigen or self tissue;
(2) evidence that
such a reaction is not secondary to tissue damage but is of
primary pathogenic significance;
(3) the absence of another
well-defined cause of the disease
Disorders in which chronic
inflammation is a prominent component are sometimes grouped
under
immune-mediated inflammatory diseases; these may be
autoimmune or the immune response may be directed against
normally harmless microbes such as gut commensal bacteria
Organ-Specific AI
Diseases Mediated by Antibodies Autoimmune hemolytic anemia Autoimmune thrombocytopenia Autoimmune atrophic gastritis of pernicious anemia Myasthenia gravis Graves disease Goodpasture syndrome
Diseases Mediated by T Cells*
Type 1 diabetes mellitus
Multiple sclerosis
Diseases Postulated to Be Autoimmune
Inflammatory bowel diseases (Crohn disease, ulcerative colitis)
Primary biliary cirrhosis
Autoimmune (chronic active) hepatitis
Systemic AI
SLE (Antibody mediated)
RA (T cell mediated)
Polyarteritis Nodosa (postulated to be AI) Inflammatory myopathy (Postulated to be AI
Immunologic Tolerance
Immunologic tolerance is the phenomenon of
unresponsiveness to an antigen-induced by exposure of
lymphocytes to that antigen
Self-tolerance
refers to lack of
responsiveness to an individual’s own antigens, and it underlies
our ability to live in harmony with our cells and tissues. Because
the antigen receptors of lymphocytes are generated by somatic
recombination of genes in a random fashion
Central Tolerance
In this process, immature self-reactive T and B lymphocyte
clones that recognize self antigens during their maturation in
the central (or generative) lymphoid organs (the thymus for T
cells and the bone marrow for B cells) are killed or rendered
harmless.
• In developing T cells
random somatic gene rearrangements
generate diverse TCRs. Such antigen-independent TCR generation produces many lymphocytes that express highaffinity receptors for self antigens.
When immature
lymphocytes encounter the antigens in the thymus, many of the
cells die by apoptosis.
This process, called negative selection or
deletion is responsible for eliminating self-reactive lymphocytes from the T-cell pool.
A wide variety of autologous
protein antigens, including antigens thought to be restricted to
peripheral tissues, are processed and presented by
thymic
antigen-presenting cells in association with self MHC molecules
and can, therefore, be recognized by potentially self-reactive T
cells
AIRE
(autoimmune regulator);
stimulates expression of some “peripheral tissue-restricted” self-antigens
in the thymus and is thus critical for deletion of immature T cells specific for these antigens.
Mutations in the AIRE gene
are the cause of an autoimmune polyendocrinopathy Ch.24
developing B cells
strongly recognize self antigens in the
bone marrow, many of the cells reactivate the machinery of
antigen receptor gene rearrangement and begin to express new
antigen receptors, not specific for self antigens. This process is
called receptor editing
How many cells are thought to have undergone Receptor editing during maturation?
it is estimated that a quarter to half of
all B cells in the body may have undergone receptor editing
during their maturation. If receptor editing does not occur, the
self-reactive cells undergo apoptosis, thus purging potentially
dangerous lymphocytes from the mature pool
Peripheral Tolerance
Several mechanisms silence potentially autoreactive T and B
cells in peripheral tissues; these are best defined for T cells.
Anergy
Lymphocytes that recognize self antigens may be rendered functionally unresponsive, a phenomenon called
anergy
also affects mature B cells in peripheral tissues. It is
believed that if B cells encounter self antigen in peripheral
tissues, especially in the absence of specific helper T cells, the
B cells become unable to respond to subsequent antigenic
stimulation and may be excluded from lymphoid follicles,
resulting in their death
activation of antigen-specific
T cells require two signals
recognition of peptide antigen in
association with self MHC molecules on the surface of APCs
and a set of costimulatory signals (“second signals”) from APCs
second signals are provided by certain T cell-associated
molecules, such as
CD28, that bind to their ligands (the
costimulators B7-1 and B7-2) on APCs.
If the antigen is
presented to T cells without adequate levels of costimulators
cells become anergic.
is that T
cells that recognize self antigens receive an inhibitory signal
from receptors that are structurally homologous to
CD28 but
serve the opposite functions
Two of these inhibitory receptors
are
CTLA-4, which (like CD28) binds to B7 molecules, and PD-1,
which binds to two ligands that are expressed on a wide variety
of cells
CTLA-4 has higher affinity for
B7 molecules
than does CD28, CTLA-4 may be preferentially engaged when
the levels of B7 are low, as when APCs are presenting self
antigens.
microbial products elicit innate immune
reactions, during which
B7 levels on APCs increase and the
low-affinity receptor CD28 is engaged more. Thus, the affinities
of the activating and inhibitory receptors and the level of
expression of B7 may determine the outcome of T cell antigen
recognition.
CTLA-4 or PD-1 is knocked out
develop autoimmune
diseases
antibodies that
block CTLA-4 and PD-1 for
tumor immunotherapy—by removing
the brakes on the immune response, these antibodies promote
responses against tumors.
Suppression by regulatory T cells. A population of T cells
called regulatory T cells functions to prevent immune
reactions against
self antigens
Regulatory T cells develop
mainly in the
thymus, as a result of recognition of self antigens
(Fig. 6-21), but they may also be induced in peripheral
lymphoid tissues
The best-defined regulatory T cells are
CD4+
cells that express high levels of CD25, the α chain of the IL-2
receptor, and a transcription factor of the forkhead family,
called FOXP3. Both IL-2 and FOXP3 are required for the
development and maintenance of functional CD4+ regulatory T
cells.
Mutations in FOXP3
result in severe autoimmunity in
humans and mice; in humans these mutations are the cause of
a systemic autoimmune disease called IPEX (an acronym for
immune dysregulation, polyendocrinopathy, enteropathy, Xlinked).
In mice knockout of the gene encoding IL-2 or the IL-2
receptor
α or β chain also results in severe multi-organ
autoimmunity, because IL-2 is essential for the maintenance of
regulatory T cells
Recent genome-wide association studies
have revealed that polymorphisms in the CD25 gene are
associated with
multiple sclerosis and other autoimmune
diseases, raising the possibility of a regulatory T-cell defect
contributing to these diseases
T Cell inhibitory activity may be mediated in part by
the secretion of immunosuppressive cytokines such as
IL-10
and TGF-β, which inhibit lymphocyte activation and effector
functions. Regulatory T cells also express CTLA-4, which may
bind to B7 molecules on APCs and reduce their ability to
activate T cells via CD28
Regulatory T cells may play a role in the acceptance of
fetus
There is
emerging evidence that regulatory T cells prevent immune
reactions against
fetal antigens that are inherited from the
father and therefore foreign to the mother. In line with this
idea, during evolution, placentation appeared simultaneously
with the ability to stably express the Foxp3 transcription factor.
Deletion by apoptosis
T cells that recognize self
antigens may receive signals that promote their death by
apoptosis
Two mechanisms of deletion of mature T cells have
been proposed, based mainly on studies in mice
It is postulated
that if T cells recognize self antigens, they may express a proapoptotic member of the Bcl family, called Bim, without
antiapoptotic members of the family like Bcl-2 and Bcl-x (whose
induction requires the full set of signals for lymphocyte
activation). Unopposed Bim triggers apoptosis by the
mitochondrial pathway
A second mechanism of
activation-induced death of CD4+ T cells and B cells involves
the Fas-Fas ligand system. Lymphocytes as well as many other
cells express the death receptor Fas (CD95), a member of the
TNF-receptor family. Fas ligand (FasL), a membrane protein
that is structurally homologous to the cytokine TNF, is
expressed mainly on activated T lymphocytes. The engagement
of Fas by FasL induces apoptosis of activated T cells (
In humans a similar disease is
caused by mutations in the FAS gene
autoimmune lymphoproliferative syndrome (ALPS).
Some antigens are hidden (sequestered) from the immune
system, because
hidden (sequestered) from the immune
system, because the tissues in which these antigens are located
do not communicate with the blood and lymph. As a result, self
antigens in these tissues fail to elicit immune responses and are
essentially ignored by the immune system. This is believed to
be the case for the testis, eye, and brain, all of which are called
immune-privileged sites
Autoimmunity
arises from a combination of the
inheritance of susceptibility genes, which may contribute
to the breakdown of self-tolerance, and environmental
triggers, such as infections and tissue damage, which
promote the activation of self-reactive lymphocytes
Defective tolerance or regulation
Fundamental to the
development of autoimmune diseases is a failure of the
mechanisms that maintain self-tolerance
• Abnormal display of self antigens
Abnormalities may
include increased expression and persistence of self antigens
that are normally cleared, or structural changes in these
antigens resulting from enzymatic modifications or from
cellular stress or injury. If these changes lead to the display of
antigenic epitopes that are not expressed normally, the immune
system may not be tolerant to these epitopes, thus allowing
anti-self responses to develop.
Inflammation or an initial innate immune response
innate immune response is a strong
stimulus for the subsequent activation of lymphocytes and the
generation of adaptive immune responses. Microbes or cell
injury may elicit local inflammatory reactions resembling innate
immune responses, and these may be critical inducers of the
autoimmune disease.
Role of Susceptibility Genes
Most autoimmune diseases are complex multigenic
disorders
The incidence of many autoimmune
diseases is greater in twins of affected individuals than in the
general population, and greater in monozygotic than in dizygotic
twins, proof that genetics contributes to the development of
these disorders.
Association of HLA Alleles with Disease
Among the genes known to be associated with
autoimmunity, the greatest contribution is that of HLA
genes
The most striking of these associations is between ankylosing spondylitis
HLA-B27; individuals who
inherit this class I HLA allele have a 100-200 fold greater chance
(odds ratio, or relative risk) of developing the disease compared
with those who do not carry HLA-B27
Association of Non-MHC Genes with Autoimmune
Diseases
Genome-wide association studies and family studies have shown
that multiple non-MHC genes are associated with various
autoimmune diseases
Polymorphisms in a gene called PTPN22,
protein tyrosine phosphatase, are associated with rheumatoid
arthritis, type 1 diabetes, and several other autoimmune
diseases
the gene
that is most frequently implicated in autoimmunity
PTPN22,
Polymorphisms in the gene for NOD2 are associated with
Crohn disease, a form of inflammatory bowel disease, especially
in certain ethnic populations. NOD2, a member of the NOD-like
receptor (NLR) family (discussed earlier), is a cytoplasmic
sensor of microbes that is expressed in intestinal epithelial and
other cells
Polymorphisms in the genes encoding the IL-2 receptor (CD25)
and IL-7 receptor α chains are associated with
multiple
sclerosis and other autoimmune diseases. These cytokines may
control the maintenance of regulatory T cells.
PTPN22
RA, T1D, IBD
Protein tyrosine phosphatase, may affect signaling in lymphocytes and may alter negative
selection or activation of self-reactive T cells
IL23R
IBD, PS (Psoriasis), AS (Ankyl. Spond)
Receptor for the TH17-inducing cytokine IL-23; may alter differentiation of CD4+ T cells into
pathogenic TH17effector cells
CTLA4
T1D, RA
Inhibits T cell responses by terminating activation and promoting activity of regulatory T cells;
may interfere with self-tolerance
IL2RA
MS, T1D
α chain of the receptor for IL-2, which is a growth and survival factor for activated and
regulatory T cells; may affect development of effector cells and/or regulation of immune
responses
NOD2
IBD
Cytoplasmic sensor of bacteria expressed in Paneth and other intestinal epithelial cells; may
control resistance to gut commensal bacteria
ATG16
IBD
Involved in autophagy; possible role in defense against microbes and maintenance of epithelial
barrier function
IRF5, IFIH1
SLE
Role in type I interferon production; type I IFN is involved in the pathogenesis of SLE
Role of Infections
Autoimmune reactions may be triggered by infections
Two mechanisms of Infections
First, infections may
upregulate the expression of costimulators on APCs. If these
cells are presenting self antigens, the result may be a
breakdown of anergy and activation of T cells specific for the
self antigens
Second, some microbes may express antigens that
have the same amino acid sequences as self antigens. Immune
responses against the microbial antigens may result in the
activation of self-reactive lymphocytes
molecular mimicry
Immune
responses against the microbial antigens may result in the
activation of self-reactive lymphocytes
A clear example of such mimicry is
rheumatic heart disease, in which antibodies against
streptococcal proteins cross-react with myocardial proteins and
cause myocarditis
Epstein-Barr virus
(EBV) and HIV
cause polyclonal B-cell activation, which may
result in production of autoantibodies.
Infections may protect against some autoimmune
diseases
Although the role of infections in triggering autoimmunity has received a great deal of attention, recent
epidemiologic studies suggest that the incidence of autoimmune
diseases is increasing in developed countries as infections are
better controlled. In some animal models (e.g., of type 1 diabetes) infections greatly reduce the incidence of disease
General Features of Autoimmune
Disease
Autoimmune diseases tend to be chronic, sometimes with relapses and remissions, and the damage is often
progressive. One reason for the chronicity is that the immune
system contains many intrinsic amplification loops that allow
small numbers of antigen-specific lymphocytes to accomplish
their task of eradicating complex infections.
The clinical and pathologic manifestations of an
autoimmune disease are determined by
nature of the
underlying immune response. Some of these diseases are
caused by autoantibodies, whose formation may be associated
with dysregulated germinal center reactions. Most chronic
inflammatory diseases are caused by abnormal and excessive
TH1 and TH17 responses; examples of these diseases include
psoriasis, multiple sclerosis, and some types of inflammatory
bowel disease.
CD8+ CTLs contribute to the killing of cells, such as
islet β cells in type 1 diabetes. In some autoimmune diseases,
such as rheumatoid arthritis, both antibodies and T cell–
mediated inflammation may be involved.
Systemic Lupus Erythematosus (SLE)
SLE is an autoimmune disease involving multiple organs,
characterized by a vast array of autoantibodies,
particularly antinuclear antibodies (ANAs), in which injury
is caused mainly by deposition of immune complexes and
binding of antibodies to various cells and tissues.
SLE is a
fairly common disease, with a prevalence that may be as high as
1 in 2500 in certain populations. Similar to many autoimmune
diseases, SLE predominantly affects women, with a frequency of
1 in 700 among women of childbearing age and a female-to-male
ratio of 9 : 1 during the reproductive age group of 17 through 55
years
female-to-male ratio is only
2 : 1 for
disease developing during childhood or after the age of 65. The
prevalence of the disease is 2- to 3-fold higher in blacks and
Hispanics than in whites
The hallmark of SLE is the
production of autoantibodies
Antinuclear antibodies (ANAs)
(1) antibodies to DNA,
(2) antibodies to histones,
(3) antibodies to nonhistone proteins bound to RNA, and
(4) antibodies to
nucleolar antigens.
ANAs is indirect immunofluorescence, which can identify
antibodies that bind to a variety of nuclear antigens, including
DNA, RNA, and proteins (collectively called generic ANAs). The
pattern of nuclear fluorescence suggests the type of antibody
present in the patient’s serum
Four basic patterns are
Homogeneous or diffuse nuclear staining Rim or peripheral staining Speckled pattern Nucleolar pattern Centromeric pattern
Homogeneous or diffuse nuclear staining
reflects
antibodies to chromatin, histones, and, occasionally, double-stranded DNA
Rim or peripheral staining
patterns are most often indicative of
antibodies to double-stranded DNA and sometimes to nuclear
envelope proteins.
Speckled pattern
refers to the presence of uniform or variable-sized speckles. This is one of the most commonly observed
patterns of fluorescence and therefore the least specific. It
reflects the presence of antibodies to non-DNA nuclear
constituents such as Sm antigen, ribonucleoprotein, and SS-A
and SS-B reactive antigens.
Nucleolar pattern
refers to the presence of a few discrete spots
of fluorescence within the nucleus and represents antibodies to
RNA. This pattern is reported most often in patients with
systemic sclerosis.
Centromeric pattern.
Patients with systemic sclerosis often
contain antibodies specific for centromeres, which give rise to
this pattern
Antibodies to double-stranded DNA and the so-called
Smith (Sm) antigens are
diagnostic of SLE
Antiphospholipid antibodies
present in 30% to 40% of lupus patients. They are actually
directed against epitopes of plasma proteins that are revealed
when the proteins are in complex with phospholipids
