What is Autoimmunity?

Formerly, people believed that all the self-reactive lymphocytes were destroyed at the time of development in thymus and bone marrow and a failure to do so led to autoimmune disorders. However, later studies revealed that not all self-reactive lymphocytes are eliminated. They circulate in the peripheral system but their functions are suppressed through clonal anergy. A breakdown in this mechanism gives rise to activation of such cells generating an immune response directed toward to the body.

Tolerance – A state of immunologic unresponsiveness to particular antigens or sets of antigens.

Central tolerance – Elimination of self-reactive lymphocytes in primary generative organs

Peripheral tolerance – Process by which self-reactive lymphocytes in circulation are eliminated or rendered anergic

Autoimmunity – An abnormal immune response against self-antigens

Autoimmune response – Can cause serious damage to cells and organs sometimes with fatal consequences

Organ Specific Autoimmune Disease

  • Immune response is generated to a target antigen unique to a single organ or gland
  • Cells are damaged by humoral or cell mediated immunity
  • Antibodies either overstimulate or block normal functioning
  • Damaged tissue are replaced by connective tissue called scar tissue
  1. Hashimoto’s Thyroiditis
  • Mostly seen in middle aged women
  • Individual produces autoantibodies and sensitized TH1 cells for thyroid antigens
  • The autoantibodies bind to several thyroid proteins like thyroglobulin and thyroid peroxide involved in iodine uptake
  • Consequently, no effective iodine uptake occurs leading to declined production of thyroid hormones, a condition called Hypothyroidism
  • Hypothyroidism gives rise to goitre
  • Binding of antibodies is accompanied by a DTH reaction due to intense infiltration of lymphocytes, macrophages and plasma cells which form lymphocytic follicles and germinal centres
  1. Autoimmune Anaemia
  • Examples – Pernicious anaemia, Haemolytic and drug – induced anaemia
  • Pernicious anaemia occurs due to autoantibodies to a membrane protein on gastric parietal cells that mediates uptake of vitamin B12 which is essential for haematopoiesis
  • In absence of vitamin B12, the number of mature functional RBCs decreases dramatically making the person anaemic
  • Individuals produce autoantibodies to RBC surface antigens either due to Rhesus antigens (as seen in haemolytic disease of new born) or binding of penicillin or methyldopa (anti-hypertensive drug) to RBC that are then recognized as antigens
  • This triggers complement mediated lysis or opsonisation and phagocytosis of the RBCs
  • These sensitized antibodies can be detected by Coomb’s test
  1. Insulin Dependent Diabetes Mellitus
  • The immune system attacks insulin producing beta cells arranged in spherical clusters called islet of Langerhans scattered in pancreas
  • Destroys beta cells, reduces insulin level simultaneously increasing blood glucose level
  • Several factors are involved in destruction of beta cells-
    • Activated CTLs migrate to the islets and begin to attack insulin producing cells. The cytokines produced by the CTLs are IFNϒ, TNFα, IL-1 etc. Activated macrophages also are involved and destroy beta cells by releasing lytic enzymes
    • Autoantibodies – Antibody mediated complement lysis or Antibody dependent cell-mediated cytotoxicity (ADCC)
  • Manifestations of diabetes – ketoacidosis, urine production, atherosclerosis vascular lesions, renal failure, blindness
  1. Grave’s Disease
  • Production of thyroid hormones – thyroxine (T4) and triiodothyronine is carefully regulated by thyroid stimulating hormone (TSH) produced by the pituitary gland
  • TSH binds to TSHR on thyroid cells activating adenylate cyclase that eventually triggers hormone synthesis in cells
  • Autoantibodies also function in the same manner. However, unlike TSH, their production is not regulated and therefore they lead to overstimulation of thyroid gland
  • Such antibodies are called LATS (long-acting thyroid stimulating) autoantibodies

Grave's disease, Hyperthyroidism, Autoimmunity

  1. Myasthenia Gravis
  • Caused by blocking antibodies
  • They bind to acetylcholine receptors (AChR) on muscle cells blocking the binding of ACh and also induces complement mediated lysis of muscle cells. Prevent contraction of muscle
  • Hence, progressive weakening of muscles
  • Signs – drooping eyelids, inability to retract corners of the mouth, movement problems

Autimmunity, Myasthenia gravis

 

Systemic Autoimmune Disease

  • Response is targeted towards a wide range of antigens
  • Involves many different tissues and organs
  • Cause of widespread tissue damage is cell mediated immune responses, autoantibodies or accumulation of immune complexes
  1. Systemic Lupus Erythematosus
  • Occurs chiefly in women of 20-40 years
  • Ratio of female:male patients is 10:1
  • Characterized by fever, weakness, arthritis, skin rash, pleurisy and kidney dysfunction
  • Individual produces autoantibodies to vast array of tissue antigens such as DNA, histones, RBCs, WBCs, platelets etc.
  • Autoantibodies for RBCs and platelets induce complement mediated lysis causing haemolytic anaemia and thrombocytopenia respectively
  • When immune complexes are deposited along the walls of small blood vessels it causes Type III hypersensitivity reaction. This activates the complement system generating MAC and complement lysis products. This damages blood vessels causing vasculitis and glomerulonephritis
  • Excessive complement activation produces high serum levels of C3a and C5a. C5a induces expression of CR3 (complement receptor 3)on neutrophils that aggregate and attach to vascular endothelium
  • As they attach the number of circulating neutrophils decline and cause vasculitis (occlusions on blood vessels)
  • Lab diagnosis –
    • Detection of antinuclear antibodies – DNA, nucleoproteins, histones, nRNA (nuclear RNA)
    • Immunofluorescence staining
  1. Multiple Sclerosis
  • Affects people of 20-40 years
  • Common cause of neurologic disability
  • Symptoms –
    • Mild – numbness in limbs
    • Severe – paralysis or vision loss
  • Individual produces self-reactive T lymphocytes that cause inflammatory lesions along the myelin sheath of neurons. Myelin sheath serves to insulate the neurons and its breakdown leads to numerous neurological dysfunctions
  • Cause is not well understood. But the likely predisposing factor is infection with virus that cause demyelinating disease
  1. Rheumatoid Arthritis
  • Occurs in 40-60 years aged women
  • Symptoms – chronic inflammation of joints, hematologic, cardiovascular and respiratory complications
  • Individual produces autoantibodies called rheumatoid factors that react with Fc region of IgG antibodies. The classic rheumatoid factor is IgM class antibody
  • IgM-G antibody complex gets deposited in the joints
  • Immune complexes activate complement system giving rise to Type III hypersensitivity reaction and chronic inflammation of joints

Continue to Part 2

AChAChRautoantibodiesautoantibodyautoimmune anaemiaautoimmune anemiaautoimmune diseaseautoimmune diseasesautoimmune disorderautoimmune disordersautoimmune responseautoimmunitybeta cellscentral toleranceclonal anergygrave's diseasehashimoto's diseasehypothyroidismIDDMinsulin dependent diabetes mellitusmultiple sclerosismyasthenis gravismyelin sheathorgan specific autoimmune diseaseperipheral tolerancerheumatoid arthritisSLEsystemic autoimmune diseasesystemic lupus erythematosusthyroid stimulating hormonetoleranceTSHTSHR
By ImmunologyLeave a Comment on Autoimmunity I – Types of autoimmune disorders

Done reading? Let me know how you liked it! :)