2. Immune reactions against self-antigens (autoimmunity ) are
an important cause of certain diseases in humans. Autoimmune
diseases may result from tissue injury caused by T cells or
antibodies , that react against self-antigens. If immune response
is directed against a single organ or tissue, resulting in
organ-specific disease: e.g,o Type I diabetes mellitus:
autoreactive T- cells and antibodies are specific for cells of
pancreatic islets.o Multiple sclerosis: autoreactive T- cells react
against central nervous system myelin.
3. generalized or systemic disease: e.g,o SLE : antibodies
directed against DNA, platelets, red cells, and
protein-phospholipid complexes ; result in wide spread lesions
throughout the body. characterized by injury to skin, joints,
kidney, and serosal membranes. In middle of spectrum is Goodpasture
syndrome in which antibodies to basement membranes of lung and
kidney , induce lesions in these organs.
4. Immunologic Tolerance: Immunologic tolerance is a state in
which the individual is incapable of developing immune response to
specific antigen. Self-tolerance refers to lack of immune response
against self antigen . autoimmunity results from the loss of
self-tolerance. Several mechanisms explain the tolerant state;
classified into two broad groups: central tolerance and peripheral
tolerance.
5. Central Tolerance: refers to deletion of self-reactive T-
and B-lymphocyte during their maturation in central lymphoid organs
(thymus for T cells, and bone marrow for B cells). Many
self-antigens may not be present in thymus, and hence T- cells
bearing receptors for such autoantigens escape into periphery.
There is similar "slippage" in B-cell system as well.
6. Peripheral tolerance: self-reactive T cells that escape
central deletion can cause tissue injury unless they are deleted in
peripheral tissues. Several mechanisms for peripheral deletion.
They include : 1. Anergy :o refers to prolonged or irreversible
inactivation of lymphocytes.o activation of T- cells requires two
signals: peptide antigen on surface of antigen-presenting cells.
costimulatory signals ("second signals") provided by
antigen-presenting cells.
7. o If the antigen is presented by cells that do not bear
costimulators, a negative signal is delivered, and T- cell becomes
anergic.o Anergy affects B- cells as well.2. Suppression by
regulatory T cells:o regulatory T cells preventing immune reactions
against self-antigens.o The best-defined regulatory T cells are
CD4+ T cells that constitutively express CD25 and the chain of IL-2
receptor.
8. 3. Clonal deletion by activation-induced cell death:o CD4+ T
cells that recognize self-antigens may receive signals that promote
their death by apoptosis.o One mechanism involves the Fas-Fas
ligand system:- CD4+ T cells express Fas (CD95). FasL, expressed
mainly on activated T lymphocytes. The engagement of Fas by FasL
induces apoptosis of CD4+ T cells.o Self-reactive B cells may also
be deleted by FasL on activated T cells engaging Fas on B
cells.
9. 4. Antigen sequestration:o Some antigens are hidden from
immune system because the tissues in which these antigens are
located do not communicate with blood and lymph as in testis, eye,
and brain.o If these antigens are released as a consequence of
trauma or infection, the result may be an immune response that
leads to tissue inflammation and injury.o This is the postulated
mechanism for post-traumatic autoimmune orchitis and uveitis.
10. Autoimmune diseases ( examples ): Systemic Lupus
Erythematosus :- SLE is a multisystem disease of autoimmune origin,
characterized by prescence of autoantibodies, particularly
antinuclear antibodies (ANAs). Anti double strands DNA antibody is
the most common ANA. it is a chronic, remitting and relapsing,
often febrile illness characterized by injury to skin, joints,
kidney, and serosal membranes. SLE is predominantly a disease of
women, usually arises in twenties and thirties
11. Etiology and Pathogenesis:Genetic Factors:o Up to 20% of
clinically unaffected first-degree relatives of SLE patients reveal
autoantibodies.o Studies of HLA system showed association of SLE
with HLA-DQ locus.Environmental Factors:o drugs such as
hydralazine, procainamide, and d-penicillamine can induce SLE-like
response .o Exposure to ultraviolet light .o Sex hormones exert an
important influence on occurrence and manifestations of SLE.
12. Immunologic Factors:o Polyclonal B-cell activation can be
demonstrated in patients with SLE .o Molecular analyses of
anti-double-stranded DNA antibodies, strongly suggest that
autoantibodies are results from an antigen-specific helper T
cell-dependent B-cell response (TH2).
13. Morphology: The lesions result from deposition of immune
complexes in blood vessels, kidneys, connective tissue, and
skin.(Type III hypersensitivity reaction ). An acute necrotizing
vasculitis involving small arteries and arterioles may be present
in any tissue. In chronic stages, vessels undergo fibrous
thickening with luminal narrowing
14. Kidney:(WHO) classification of lupus nephritis, five
patterns arerecognized:(1) minimal or no detectable abnormalities
(class I)(2) mesangial lupus glomerulonephritis (class II)(3) focal
proliferative glomerulonephritis (class III)(4) diffuse
proliferative glomerulonephritis (class IV)(5) membranous
glomerulonephritis (class V)Skin:Characteristic erythema affects
the facial butterfly area(bridge of nose and cheeks) in
approximately 50% ofpatients (facial butterfly skin rash ).
15. Joints:Non-erosive arthritis with little deformity.Central
Nervous System:Focal neurologic symptoms.Cardiovascular
system:Mainly pericarditis.Myocarditis is less common.Nonbacterial
verrucous endocarditis ( Libman-sacksendocarditis ).Lungs:Pleuritis
and pleural effusions .
16. Rheumatoid Arthritis: chronic inflammatory disease affects
primarily joints(erosive arthritis), but may involve
extra-articular tissues such as skin, blood vessels, lungs, and
heart. About 1% of worlds population is affected. women two to
three times more than men. most common in age 40 to 70, but no age
is excluded. The autoimmune reaction consists of activated CD4+ T
cells, and probably B lymphocytes as well (Type IV, and Type II
H.S.R. ). Many patients have serum Rheumatoid factor (IgM antibody
reactive with Fc portion of patients own IgG). HLA DRB1
association.
17. Sjgren Syndrome : chronic disease characterized by dry eyes
(keratoconjunctivitis sicca) and dry mouth (xerostomia) resulting
from immunologically mediated destruction of lacrimal and salivary
glands. It occurs as an isolated disorder (primary form) also known
as sicca syndrome; or more often in association with another
autoimmune disease (secondary form). Among the associated disorders
rheumatoid arthritis is the most common, but some patients have
SLE, polymyositis, or scleroderma.
18. About 75% of patients have rheumatoid factor regardless of
whether coexisting rheumatoid arthritis is present or not. Most
important are antibodies (ANAs)directed against two
ribonucleoprotein antigens SS-A (Ro) and SS-B (La) which can be
detected in up to 90% of patients. These autoantibodies are also
present in patients with SLE and hence are not pathognomonic of
Sjgren syndrome. Sjgren syndrome shows association with HLA-B8,
HLA-DR3, and DRW52 genetic loci.
19. Systemic Sclerosis (Scleroderma): chronic disease of
unknown etiology, characterized by abnormal accumulation of fibrous
tissue in skin and multiple organs. The skin is most commonly
affected, but gastrointestinal tract, kidneys, heart, muscles, and
lungs also are frequently involved. Death from renal failure,
cardiac failure, pulmonary insufficiency, or intestinal
malabsorption . Two major categories: (1) Diffuse scleroderma:
widespread skin involvement at onset, with rapid progression and
early visceral involvement.
20. (2) Limited scleroderma: skin involvement is often confined
to fingers, forearms, and face. Visceral involvement occurs
late.Etiology and Pathogenesis: The cause is not known. The trigger
for excessive fibrosis is a combination of abnormal immune
responses and vascular damage, resulting in local accumulation of
growth factors that act on fibroblasts and stimulate collagen
production. Although T cell-mediated fibrogenesis and vascular
injury are important ( type IV H.S.R) , but activation of humoral
immunity is important as well.
21. Virtually all patients have ANAs. Two ANAs unique to
systemic sclerosis :o One directed against DNA topoisomerase I
(anti-Scl 70) is highly specific present more in patients with
diffuse systemic sclerosis.o The other anti centromere antibody, is
found more in patients with limited systemic sclerosis.o The
majority of patients with anticentromere antibody have the CREST
syndrome.o It is rare to have both antibodies in the same
patient.
22. Inflammatory Myopathies: uncommon, heterogeneous group of
disorders characterized by injury and inflammation of skeletal
muscles, which are probably immunologically mediated. Three
distinct disorders: Dermatomyositis, Polymyositis, and
Inclusion-body myositis. These may occur alone or with other
immune-mediated diseases, particularly systemic sclerosis. Anti
Histidyl-t-RNA synthetase antibody (Jo-1 )which is ANA is
common.