BIOLOGY- MANAGEMENT OF IMMUNE SYSTEM

The immune system

The immune system has evolved to protect the body against foreign bacteria and viruses. The innate immunity consists of cells which are inherently capable of detecting thousands of patterns of antigens on bacterial walls  as well as antigen patterns of dead and necrotic cell components.The patterns are detected by receptors called Toll like receptors and NOD like receptors present on macrophages and  dendritic cells.On detection they produce cytokines and generate the inflammatory reaction which destroys the bacteria and interferon for viruses,

  Adaptive immunity has unlimited pattern recognition ability . This is so because the B cell receptors and T cell receptors present on lymphocytes can undergo somatic rearrangements to produce these patterns during development. The various receptor patterns occur in B lymphocytes in bone marrow and Thymus for T cells.The TCR on T lymphocytes of type CD 8+  can recognise extra cellular antigens on bacteria in combination with cell membrane proteins called MHC 1 and.subsequently with help of antigen presenting cells  lyse them.( Cytotoxic T cells). Another T cells type with TCR called CD 4+ with help of cell membrane proteins MHC type 2and B cells enable production of antibodies to intra cellular pathogens.( Helper T cells). The MHC proteins are produced by genes inside lymphocytes called MHC. These genes are unique to every individual. Their importance lies in B cell production of antibodies which depend on rearrangemen5 of the protein products of MHC gene to produce unlimited variants of antibodies. 

Immunological tolerance

The immune system is prevented from acting against sef antigens by a number of mechanisms.Central  T cell tolerance occurs in lymphocytes when they are developing in thymus. The T cells with receptors against self antigens undergo apoptosis or undergo transformation to regulatory T cells. Immature T cells when exposed to self antigens are deleted in thymus.. In periphery tolerance of mature T lymphocytes occurs by anergy ,apoptosis and regulatory T cells,Anergy occurs because in periphery absence of co stimulation by APC involving B7 molecules by CD28+ receptors precludes activation of Tcells.

Apoptosis occurs because of activation of ubiquity ate protien which target them for lysosomal degradation.Repeated exposure to self antigens in absence of protien bim causes apoptosis. AlsoInhibitory molecules like CTL-4 and PD-1 are stimulated in regulatory T cells by self antigens. These block  CD28 receptor and also reduce the availability of costimulant B7.

 Regulatory T cells are formed in presence of self antigens and require presence of TGF-beta and IL -2. They produce tolerance by producing TGF-beta which in turn inhibits differentiation of effector T cells and activation of macrophages. Also production of IL-10 inhibits costimulators and APC .

Autoimmune diseases

A breakdown in immune tolerance can result in the immune system damaging own body cells . There are four types of autoimmune diseases: In Type 1 T helper cells bind extrinsic molecules ,called allergens and secrete IgE immunoglobulin. The IgE binds to mast cells which release vasoactive amines, lipid mediators and cytokines. These molecules cause a local allergic reaction or systemic anaphylaxis consisting of brochospasm,hypotension and even death. 

In Type 2 auto immunity antibodies are produced against body cells which fix to body cells and activate complement mediated cell destruction.Examples are haemolytic anaemia and good pasture syndrome ( lungs and kidney) They can be directed against membrane receptors and cause cell dysfunction as occurs in myasthenia gravies and Graves’ disease. 

In Type 3 autoimmune diseases antibodies are produces against self antigens leading to immune complex formation which circulate in blood and get deposited in various organs causing local damage by complement activation. Generally the organs damaged during circulation are kidneys,joint fluids,blood vessels( vasculitis). Diseases resulting include SLE,Polyarteritis nodosa,post streptococcal glomerulonephritis

 In Type 4 autoimmune disease T cells are involved against self antigens and damage cells by cytotoxic Tcells. Example include chronic tuberchulosis, rheumatoid arthritis, systemic sclerosis,Type 1 DM

Mechanism of autoimmune diseases

Autoimmunity results from breakdown of loerance .The mechanisms include loss of central immune tolerance due to T cells surviving in presence of self antigens in Thymus. This may involve a genetic defect in apoptosis.Next ,the most common cause is a defect in T regulatory cells which normally suppress  T cell activation in presence of self antigens due to lack of costimalation by APC. Thirdly there maybe absence of inhibitory molecules. There may in addition be abnormal display of self antigens that are normally cleared. Chronic inflammation may also lead to activation of APCwhich can overcome T cell regulation. In most cases there is found some defect in HLA genes leading to the disease.These genes probably predispose to autoimmunity by giving defective signal to T regulatory cells

Ack: Robbins Basis pathology; Cellular and molecular immunology