Transcript autoimmune diseases. Autoimmune diseases

Chapter 19
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Autoimmunity. Failure of the normal mechanisms of self-tolerance results in reactions
against one’s own cells and tissues that are called autoimmunity. The diseases caused by
autoimmunity are referred to as autoimmune diseases. Autoimmune diseases are estimated
to affect 2% to 5% of the population in developed countries, and the incidence of these
disorders is rising
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Reactions against microbes. Immune responses against microbial antigens may cause
disease if the reactions are excessive or the microbes are unusually persistent. Also, immune
complexes, which deposit in tissues and trigger inflammation. Rarely, antibodies or T cells
against a microbe may cross-react with a host tissue. Also, CTLs try to eliminate infected
cells, and this normal immune response damages liver cells
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Reactions against environmental antigens. Most healthy individuals do not react against
common, generally harmless environmental substances, but almost 20% of the population is
abnormally responsive to one or more of these substances. These individuals produce IgE
antibodies that cause allergic diseases
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DISEASES CAUSED BY ANTIBODIES
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Immune Complex–Mediated Diseases
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Serum Sickness
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Immunization of an animal such as a rabbit with a large dose of a foreign protein antigen
leads to the formation of antibodies against the antigen. These antibodies bind to and form
complexes with circulating antigen, which are initially cleared by macrophages in the liver
and spleen. As more and more antigen-antibody complexes are formed, some of them are
deposited in vascular beds
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Because the complexes are deposited mainly in small arteries, renal glomeruli, and the
synovia of joints, the clinical and pathologic manifestations are vasculitis, nephritis, and
arthritis
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More indolent and prolonged disease, called chronic serum sickness, is produced by
multiple injections of antigen, which lead to the formation of smaller complexes that are
deposited most often in the kidneys, arteries, and lungs
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Arthus Reaction
It is induced by injection of an antigen subcutaneously into a previously immunized animal
or an animal that has been given intravenous antibody specific for the antigen. Circulating
antibodies rapidly bind to the injected antigen and form immune complexes that are
deposited in the walls of small arteries at the injection site. This deposition gives rise to a
local cutaneous vasculitis with tissue necrosis.
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SLE is a chronic, remitting and relapsing, multisystem autoimmune disease that affects
predominantly women, with an incidence of 1 in 700 among women between the ages of 20
and 60 years (about 1 in 250 among black women) and a female-to-male ratio of 10 : 1
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Constitutional / or from inflammation in various organ systems
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Organ systems may be involved singly or in any combination
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Involvement of vital organs, kidneys and CNS , accounts for significant morbidity and
mortality
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Morbidity and mortality result from: tissue damage due to the disease process or its
therapy
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Fever, anorexia, weight loss, malasia, fatigue
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Skin disease or arthritis are common in SLE
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The malar rash of acute lupus may be flat (malar blush) or slightly raised (butterfly
eruption) and Annular rash
diffuse proliferative glomerulonephritis (WHO class IV)
membranous glomerulonephritis (WHO class V)
The most frequent are antinuclear, particularly anti-DNA antibodies; others include
antibodies against ribonucleoproteins, histones, and nucleolar antigens
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Odds ratio (relative risk) for individuals with HLA-DR2 or HLA-DR3 is 2 to 3, and if both
haplotypes are present, the odds ratio is about Genetic deficiencies of classical
pathway complement proteins, especially C1q, C2, or C4, are seen in about 10% of
patients with SLE
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A polymorphism in the inhibitory Fc receptor FcγRIIB has been described in some
patients
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New hypotheses of the pathogenesis of SLE exposure to IFN-α, a type I interferon that
is produced mainly by plasmacytoid dendritic cells and TLRs that recognize DNA and
RNA, notably the DNA-recognizing TLR9, play an important role in the activation of B
cells specific for self nuclear antigens
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New Therapies for SLE, anti–IFN-α antibodies, inhibit TLR signals, depleting B cells by
use of an antibody against the B cell surface protein CD20, blocks the B cell growth
factor BAFF is now approved
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The systemic vascuilitis is a hetrogenous group of clinicopathologic entities
characterized by inflammation and damage to the blood vessels
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Most of the vasculitic syndromes are mediated by immunopathologenic
mechanism
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In some other forms; due to infection, malignan lymphoma, radiation,
transplantation, hypersensivity play little or no role.
 Type III Hypersensivity
Polyarteritis nodosa (PAN)
Henoch-Schoenlein purpura
Essential Mixed Cryoglobulinemia
Poststreptoccocal Glomerlonephritis
(PSGN)
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DISEASES CAUSED BY T LYMPHOCYTES
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RA is an inflammatory disease involving small and large joints of the extremities, including
fingers, shoulders, elbows, knees, and ankles
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Both cell-mediated and humoral immune responses may contribute to development of
synovitis. CD4+ TH1 and TH17 cells, activated B lymphocytes, plasma cells, and
macrophages as well as other inflammatory cells are found in the inflamed synovium, and in
severe cases, well-formed lymphoid follicles with germinal centers may be present.
Numerous cytokines, including IL-1, IL-8, TNF, IL-6, IL-17, and IFN-γ, have been detected
in the synovial (joint) fluid
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Patients frequently have circulating IgM or IgG antibodies that react with the Fc (and rarely
Fab) portions of their own IgG molecules. These autoantibodies are called rheumatoid
factors (RF), and their presence is used as a diagnostic test for RA. RF may participate in the
formation of injurious immune complexes, but their pathogenic role is not established.
Another type of antibody that has been detected in at least 70% of patients is specific for
cyclic citrullinated peptides (CCP), anti- CCP
Rheumatoid Factor
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Most common autoantibody in RA
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Detected in 70-80% of RA patients
Bind to FC portion of IgG molecule
Usually an IgM antibody
Less often an IgA or IgG antibody
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High titer predicts adverse outcome
erosive arthritis, vasculitis
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Susceptibility to RA is linked to the HLA-DR4 haplotype and also an association with the
gene encoding a tyrosine phosphatase, PTPN22
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The identification of anti-CCP immune responses has led to new ideas about the pathogenesis
of RA
New Therapies for RA are antagonists
against TNF, An IL-1 antagonist and an
antibody against the IL-6 receptor are
approved treatments, as is a fusion protein of
the extracellular domain of CTLA-4 and the
Fc portion of IgG, which binds to B7
molecules and blocks B7:CD28 interactions.
Antibodies that block IL-17 are in clinical
trials. The B cell–depleting anti-CD20
antibody is of benefit in some patients
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MS is an autoimmune disease of the CNS in which CD4+ T cells of the TH1 and TH17
subsets react against self myelin antigens, resulting in inflammation in the CNS with
activation of macrophages around nerves in the brain and spinal cord, destruction of the
myelin, abnormalities in nerve conduction, and neurologic deficits
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MS is characterized clinically by weakness, paralysis, and ocular symptoms with
exacerbations and remissions; CNS imaging suggests that in patients with active disease,
there is frequent new lesion formation. The disease is modeled by experimental autoimmune
encephalomyelitis (EAE)
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EAE is induced by immunizing animals with antigens normally present in CNS myelin, such
as myelin basic protein, proteolipid protein, and myelin oligodendrocyte glycoprotein, with
an adjuvant containing heat killed mycobacterium, which is necessary to elicit a strong T cell
response
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EAE is caused by activated, CD4+ TH1 and TH17 cells specific for protein antigens in
myelin. By analogy with the experimental disease, MS is also thought to be caused by myelin
specific TH1 and TH17 cells, and these cells have been detected in patients and isolated from
the blood and CNS
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Genetic polymorphisms associated with MS include the HLA locus, with HLA-DR2 and IL-2
receptor α chain, CD25
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Regulatory T cells are defective in MS patients
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New Therapies for MS, administration of β-interferon, a random polymer of four amino
acids which is postulated to bind to HLA molecules and block antigen presentation, an
antibody against the VLA-4 integrin, Another recently approved drug to treat MS also
interferes with leukocyte migration called fingolimod (FTY720), blocks the sphingosine 1phosphate–mediated pathway of T cell egress from lymphoid tissues
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Several mechanisms may contribute to β cell destruction, including inflammation mediated
by CD4+ TH1 cells reactive with islet antigens (including insulin), CTL-mediated lysis of
islet cells, local production of cytokines (TNF and IL-1) that damage islet cells, and
autoantibodies against islet cells and insulin
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Between 90% and 95% of Caucasians with type 1 diabetes have HLA-DR3, or DR4, or both
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An informative animal model of the disease is the non-obese diabetic (NOD) mouse
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New Therapies for IDDM inducing tolerance with diabetogenic peptides from islet antigens
(such as insulin) or generating or giving regulatory T cells to patients.
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Consists of two disorders, Crohn’s disease and ulcerative colitis, in which T cell– mediated
inflammation causes intestinal injury. Crohn’s disease is characterized by chronic
inflammation and destruction of the intestinal wall, with frequent formation of fistulas. In
ulcerative colitis, the lesions are largely confined to the mucosa and consist of ulcers with
underlying foci of inflammation. New therapies for these diseases include antibodies against
TNF, IL-17, and the p40 chain of IL-12 and IL-23.
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In immune-mediated inflammation, TH1 and TH17 cells secrete cytokines that recruit and
activate leukocytes. IL-17, produced by TH17 cells, promotes neutrophil recruitment; IFN-γ,
produced by TH1 cells, activates macrophages; and TNF and chemokines, produced by T
lymphocytes and other cells, are involved in the recruitment and activation of many types of
leukocytes. Tissue injury results from the products of activated neutrophils and macrophages,
such as lysosomal enzymes, reactive oxygen species, nitric oxide, and proinflammatory
cytokines
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T cell reactions against microbes and other foreign antigens may also lead to inflammation
and tissue injury at the sites of infection or antigen exposure
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A variety of skin diseases that result from topical exposure to chemicals and environmental
antigens, called contact sensitivity, are due to inflammatory reactions. Examples of contact
sensitivity include the rashes of poison ivy and poison oak (in which T cells react against
chemicals made by the plants called urushiols) and rashes induced by contact with a variety
of chemicals, such as thiuram, which is used in the manufacture of latex gloves
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DTH is an injurious cytokine-mediated inflammatory reaction resulting from the
activation of T cells, particularly CD4+ T cells
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The reaction is called hypersensitivity because it reflects excessive (i.e., injurious) immune
responses (which are reflections of sensitivity to an antigen) and delayed because it typically
develops during 24 to 48 hours after antigen challenge
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Subsequent exposure to the same antigen (called challenge) elicits the reaction. For example,
purified protein derivative (PPD), a protein antigen of Mycobacterium tuberculosis, elicits
a DTH reaction, called the tuberculin reaction
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Chronic DTH reactions can develop if a TH1 response to an infection activates
macrophages but fails to eliminate phagocytosed microbes. If the microbes are localized in a
small area, the reaction produces nodules of inflammatory tissue called granulomas
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CTL responses to viral infection can lead to tissue injury by killing infected cells, even if the
virus itself has no cytopathic effects
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CTLs may contribute to tissue injury in autoimmune disorders that are caused primarily by
CD4+ T cells, such as type 1 diabetes
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Myocarditis with infiltration of the heart by CD8+ T cells develops in mice and sometimes
in humans after infection with coxsackievirus B, resulting in a form of dilated
cardiomyopathy
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Anti-inflammatory Agents: corticosteroids
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Depletion of Cells and Antibodies: anti-CD20 antibody (rituximab),
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Agents Inhibit Cell-Cell Interactions in Immune Responses: block B7 costimulators for
RA and SLE
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Intravenous IgG: Large doses one possibility is that the IgG binds to the inhibitory F
receptor (FcγRIIB) on macrophages and B lymphocytes and thus attenuates inflammatory
responses. IVIG may also compete with pathogenic antibodies for binding to the neonatal Fc
receptor (FcRn),
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More specific treatment, such as inducing tolerance in disease-producing T cells or inducing
regulatory T cells specific for self antigens in multiple sclerosis and type 1 diabetes