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Autoimmunity
Prof M.I.N. Matee
Department of Microbiology and Immunology
School of Medicine
MUCHS
Autoimmunity
Immunologic tolerance Body develops a tolerance for own tissue
and does not produce a rejection response
Autoimmunity Tolerance to own tissues is lost and host
produces an immunologic rejection of own tissue
AUTOIMMMUNITY & AUTOIMMUNE DISEASES
Any body protein and many carbohydrates and lipids, as well as nucleic acids are potential antigens.
The body is capable of constructing T-Cell receptors (TCRs) or B-Cell receptors (BCRs) that can recognise these antigens and initiate an immune response against them.
Mechanisms & Causes of Autoimmunity
The occurrence of autoimmune diseases indicates the presence in the body of autoreactive lymphocyte clones which can, under certain circumstances, become activated.
a) Some self molecules are expressed at levels below the sensitivity threshold of lymphocytes.
b) Some molecules are protected by a barrier from contact with lymphocytes.
c) Some epitopes are normally hidden from the immune system and tolerance towards them is not established.
d) Autoreactive clones made tolerant by anergization can be reactivated under some circumstances.
e) Some autoreactive clones may be kept in check by regulatory mechanisms involving, for example, the suppressor T cells, and when these mechanisms fail the clones may become active.
Autoimmunity - Possible mechanisms
Sequestered antigens antigens lack access to antibody forming cells
Modified cross-reacting antigens fragmentation and recombination of antigens
Forbidden clone/clonal anergy lymphocytes developed in fetus against an
autoantigen and not eliminated Immunological deficiency
anti-idiotype and T-cell suppression not functioning
Molecular Mimicry
The main assumption of the molecular mimicry hypothesis is that some epitopes on foreign antigens are sufficiently similar to certain self epitopes to become target of immune response elicited by the former.
Uncovering of Sequestered Antigens or Cryptic epitopes
An injury or infection may temporarily release molecules normally inaccessible to the immune mechanism, which can then stimulate autoimmune attack on the cell carrying them.
Activation of Potentially Autoreactive T-Cell clones by superantigens:
Autoimmune reaction can also be triggered by superantigens, produced by some microorganisms.
Genetic Factors
Familial associations and susceptibility of inbred mouse strains to certain autoimmune diseases indicate that the development of autoimmunity depends on genetic factors.
Failure of Immune Regulation
Some autoimmune diseases are caused by an impairment of negative regulatory T cells (T-suppressor cells) that normally inhibit potentially autoreactive clones.
Causes of Tissue Damage
Autoimmunity develops into a disease when components of the immune system begin to damage the body. The mechanisms of tissue damage vary according to the types of autoimmune disease.
Examples of Autoimmune Diseases
Diseases Caused Mainly by Autoantibodies.
SLE: Systemic Lupus Erythematosus, Autoantibodies produced against DNA and other nuclear components.
Grave’s disease (Hyperthyroidism)
Autoantibodies produced against the thyroid-stimulating hormone (TSH) receptor that mimic the action of TSH and stimulate excessive production of thyroid hormones (T4, T3).
Hashimoto’s disease (Hypothyroidism)
Autoantibodies produced against thyroid antigens such as thyroglobulin.
Pernicious Anemia
Caused by autoantibodies against intrinsic factor, a membrane protein of intestinal epithelial cells, which is involved in transport of Vitamin B12.
Atrophy of the mucosal cells of the stomach and infiltration of lymphoid tissue
Diseases caused by autoreactive T cells
Insulin-dependent diabetes mellitus.
In IDDN, insulin-producing cells of the pancreatic islets of Langerhans are destroyed by CD8+ Tc cells.
Rheumatoid Arthritis.
The disease is probably caused by TH1 CD4+ cells reacting with fragments of joints antigens such as collagen or a heat shock protein bound to MHC class II molecules.
Autoimmune Diseases - Hematological
Autoimmune Hemolytic Anemia Two types
Warm Cold
May be secondary to another immune disease or idiopathic
Autoimmune DiseasesHematological
Warm Autoimmune Hemolytic Anemia Sometimes minimal but may be life
threatening RBC are sensitized with IgG, C’ or both Selective immunodeficiency seems to
predispose to the disease - may have other autoimmune conditions - may be associated with other abnormal hematological disorders
Transfusion problems
Autoimmune DiseasesHematological
Cold Autoimmune Hemolytic Anemia Acute and transient or chronic forms Acute often follows an infection from
Mycoplasma, viruses, hepatitis, syphillis Chronic form found in older people and the
anemia is worse in the winter. Testing - cold agglutinin test
dilute patient’s serum and react with patient’s cells
Autoimmune DiseasesHematological
Paroxysmal Nocturnal Hemoglobinuria C’3 activation and destruction of cells Activation occurs in acidic environment
Addison’s Disease
Lymphocytic infiltration of the adrenal gland and antibodies to adrenal cells
Often associated with thyroid disease, pernicious anemia and diabetes
Tests - Complement fixation and immunoflourescent immunologic demonstration of antibodies
Autoimmune DiseasesEndocrine System
Thyroid diseases Hashimoto Thyroiditis
lymphoid invasion of thyroid gland and resulting hypothyroidism
Antibodies against cellular thyroid elements and thyroglobulins
Grave’s Disease Antibody that mimics TSH causes hyperplasia of
the thyroid also causes exopthalmus Tests
Detection of thyroid antibodies
Autoimmune DiseasesGastrointestinal Tract
Ulcerative Colitis Inflammatory disease of the colon and
rectum/ allergy or cell mediated often associated with other autoimmune
diseases Some have antibodies against sterile
fetal colon tissue detected with immunoflourescence
Autoimmune DiseasesNeuromuscular
Myasthenia Gravis Acetylcholine is prevented from
stimulating muscle to contract Antibodies to acetylcholine receptors and
thymus abnormalities
Autoimmune DiseasesNeuromuscular
Multiple sclerosis demyelination of the white matter of the
central nervous system presence of lymphocytes in the early
lesions and plasma cells, lymphocytes and macrophages in later lesions
Testing for increased IgG levels in CSF
Autoimmune DiseasesLiver
Primary Biliary Cirrhosis affects the small intrahepatic bile ducts and
eventually leads to liver failure presence of high titer anti-mitochondrial
antibody Chronic Active Hepatitis
Infiltration of lymphocytes and plasma cells Diminished number and function of suppressor
T cells and presence of autoantibodies to different organs
Autoimmune Diseases
Goodpasture’s Syndrome Glomerularnephritis and pulmonary
damage Antibodies against basement membrane
Bullous Skin Disease Antibodies against intercellular bridges of
the cells in the epidermis
GROUP A BETA HEMOLYTICSTREP SEQUELAE
Glomerulonephritis often follows infection with Group A types
12, 4, or 49 and occurs approximately 10 days after throat infection and 20 days after skin infections
Cause may be due ag-ab immune complex at the glomerular membrane which activates complement and causes destruction
GROUP A BETA HEMOLYTICSTREP SEQUELAE
Rheumatic Fever Follows multiple infections with different
types of Group A Beta Hemolytic Strep Includes inflammation and injury to the
joints, heart and central nervous system. Possibility of a cross reacting antibody or
modified antigen which results in damage