Immunology

Dr. Ziyad 4 -10-2018

Autoimmune Diseases
*These are diseases caused by an immune reaction against self-Ag.
* They may involve single organ or be multisystemic.
*Affecting mainly female.

Immunological Tolerance

Self- Tolerance refers to a lack of immune responsiveness to one's own tissue antigens
Central tolerance. This refers to deletion of self-reactive T and B lymphocytes during their maturation in central lymphoid organs (i.e., in the thymus for T cells and in the bone marrow for B cells).
Peripheral tolerance. Self-reactive T cells that escape negative selection in the thymus can potentially dangerous unless they are deleted.
Several mechanisms in the peripheral tissues that silence autoreactive T cells
have been identified:
Anergy: This refers to functional inactivation (rather than death) of lymphocytes induced by encounter with antigens under certain conditions.
Suppression by regulatory T cells: The responses of T lymphocytes to self-antigens may be actively suppressed by regulatory T cells (Treg).
Activation-induced cell death: apoptosis of mature lymphocytes as a result of self-antigen recognition.

Mechanisms of autoimmune disease

A) Loss of self - tolerance
1- Bypass of helper T- cell tolerance: by
A/modification of molecule: if self-antigen is modified due to drugs or microorganisms, this recognized by T cells as a foreign antigen so cooperate with B cells leading to formation of autoantibodies as in autoimmune hemolytic anemia
B/expressions of costimulatory molecules: as in infection which can activate macrophages to express costimulatory molecules and present self-antigens
2- Molecular mimicry:
some infectious agent share epitopes with self-antigens so cross reaction with self-antigen is result as in rheumatic heart disease
3- Polyclonal lymphocyte activation:
some of autoreactive lymphocytes that were not deleted during development may become stimulated by antigen independent mechanisms as in endotoxins of bacteria induced polyclonal antibody against self antigens
4- Imbalance of suppressor-Helper T-cell function:
loss of suppressor T cell function or
excessive helper T cell function result in B cell activation
5- Emergence of sequestered antigens:
Some antigen are anatomically segregated from the developing immune system so clonal deletion or anergy fails to occur, if they release into circulation they induced an immune response e.g., ocular antigens
B) Genetic factors in autoimmunity
They play significant role in the predisposition to autoimmune diseases. The evidence for that are:
1-Familial clustering of several human autoimmune diseases e.g., SLE, autoimmune hemolytic anemia, & autoimmune thyroiditis .
2-Linkage of several autoimmune diseases with HLA esp. class II.
3-Induction of autoimmune diseases in transgenic rats by introduce certain human HLA e.g., HLA-B27
C) Microbial agents in autoimmunity
Included bacteria, mycoplasma , & viruses
mechanisms are:
1-association of microbial antigens & autoantigens forming new immunogenic units & by pass T-cell tolerance
2-Induction of nonspecific polyclonal B-cell mitogens & formation of Autoantibodies
3-loss of suppressor T cell function
4-Cross reaction with self-antigens


Systemic Lupus Erythromatosus
Definition: - multisystem disease of autoimmune origin, acute or gradual in onset, chronic, remitting & relapsing febrile illness characterized principally by injury to the skin, joint, kidney & serosal membranes. Female: male ratio 9:1.Age group 20-40 years.
* Four out of 11 clinical or laboratory criteria must be present for diagnosis of SLE:
(1) Malar rash.
(2) Discoid rash.
(3) Photosensitivity.
(4) Oral ulcers.
(5) Arthritis.
(6) Serositis.
(7) Renal disorders.
(8) Neurological disorders (seizures, psychosis).
(9) Hematological disorders (cytopenia, hemolytic anemia).
(10) Immunological disorder (Ab to DNA or anti-Sm, antiphospholipid Ab).
(11) Antinuclear Ab.

Etiology & pathogenesis

1- Immunologic Factors:
Autoantibodies result from hyperactivity of B cell which occur as a result of
A/ intrinsic defect in B cells
B/ excessive stimulation by helper
C/ Defect in suppressor T cell function
ANA are directed against several nuclear Antigens & categorized into:
(1) Ab against DNA. (2) Ab to histones.
(3) Ab to non histone proteins bound to RNA (smith Ag, SS-A, SS-D).
(4) Ab to nucleolar Ag.
2- Genetic factors:
high rate of concordance (30%) in monozygotic twins
family members have an increased risk of developing SLE & even may
show autoantibodies
Association between SLE & HLA-DQ locus
6 % of patients have inherited deficiencies of complement components
3- Non genetic factors:
occurrence of SLE in patients received certain drugs as procainamide &
hydralazine
Sex hormones esp. estrogen
Ultraviolet light exposure
Characteristic morphological finding in SLE:
*Skin: granular deposition of immune complex along the epidermal-dermal basement membrane producing maculopapular eruption over the malar eminencies & bridge of the nose producing butterfly pattern
*Appearance of LE bodies (hematoxylin bodies), nuclei of damaged cells react with ANAs loss their chromatin pattern and become homogenous.
*LE bodies in vitro engulfed by macrophages or neutrophils forming LE cells
*LE cells positive in 70 % of patients
*Acute necrotizing vasculitis affecting small arteries & arterioles esp.. of skin & muscles
* Kidney: deposition of immune complex in glomerular blood vessels & tubules.
*joint involvement: swelling & inflammation
* Heart: immune complex deposition on the value especially mitral value.
* spleen: marked perivascular fibrosis giving onion-skin lesion


Cardiac pathology of SLE:
* Pericarditis (most common).
* Endocarditis (Libman-Sacks).
* Nonspecific myocarditis.
* Accelerated coronary atherosclerosis