What are the hypothesized mechanisms involved with the breakdown of tolerance?
Failure to delete autoreactive lymphocytes (central and peripheral tolerance failure)
Molecular Mimicry (foreign ag so closely resembles a self-ag that Ab produced against against the foreign ag attackes the self-ag.) (e.g Rheumatic fever and acute glomerulonephritis)
Abnormal presentation of self-ag
epitope spreading
polyclonal lymphocyte activation
What is an epitope?
Epitope = a specific part of an Ag that attaches itself to a specific aby.
T-Cells: -where do these cells mature? -provide what type of immunity? -function
T cells mature in the thymus.
Provide cellular immunity, which is part of our adaptive immunity.
Function:
- induce B cells to produce antibodies
- T reg cells & T helper cells, Tcytotoxic cells
What is the difference between adaptive and innate immunity??
Innate immunity: NK, Dendritic Cells, and MFs;
- first line defense, less specific response
- present before an infection
Adaptive immunity: T and B cells
- acts to an antigenic challenge, second line defense
- memory response
- diversity
- present 5-6d post initial exposure to Ag.
What is the difference between humoral and cellular immunity?
Homoral: B cells & complement, attack ags by producing abys.
Cellular: T cells attack ags by using their cellular contents.
Describe T cell activation.
What is HLA?
CD4 and CD8 can be found in which cells? What MHC does CD4 and CD8 bind to?
Dendritic cells and Mfs (APC) present Ags to T cells via MHC complexes(on the APC).
HLA = human leukocyte antigen = gene complex encoding the major histocompatibility complex (MHC)
CD4 is found on Thelper cells. CD8 is found on Tcytotoxic cells.
MHC 2 binds with cells expressing CD4. MHC 1 binds with cells expressing CD8.
MHC Class I recognize endogenous or exogenous antigens? MHC class II??
Where are B cell located?
Function of B cells?
MHC class I recognizes endogenous antigens and MHC II recognizes exogenous antigens.
B cells can be found in the bone marrow, lymph nodes, spleen, tonsils, and peyers patches.
B cell function:
-form plasma cells and secrete immunoglobulins
What is immunological tolerance? Self- tolerance?
WHat occurs with B-cell tolerance? What conditions are associated with this?
How do we filter out autoreactive B-cells?
Tolerance = a state of unresponsiveness specific for a particular ag.
Self-tolerance: prevents the body from attacking itself.
B-cell tolerance leads to development of autoantibodies. Hyperthyroidism in Graves dz is d/t autoantibodies to TSH.
Filter out autoreactive B cells:
- clonal deletion in bone marrow
- deletion of autoreactive cells in spleen or LNN
- functional inactivation by anergy (=absence of normal immune response to a particular ag)
- receptor editing- process that changes specificity of B-cell receptor when autoantigen is encountered.
Tcell Tolerance:
- describe positive and negative selection.
- some self-reactive Tcells escape the thymus, how do we deal with this?
Positive selection: immature T cells of a clone that are not auto-reactive T cells are allowed to mature.
Negative selection: immature t-cell clones that have high affinity for host cells are sorted out and undergo apoptosis.
Escaping the thymus:
- sometimes theres no problem b/c the Tcell that escapes is immunologically ignorant b/c they cant see their Ag.
- Peripheral activation of T cell requires 2 signals; recognition of Ag with MHCs on APC AND secondary costimulatory signasl which are often absent*
- apoptosis (Fas receptor + Fas ligand)
- suppressor T cells can also down-regulate autoreactive T cells
Define:
- central tolerance
- peripheral tolerance
- anergy
Central: elimination of self-reactive T and B cells in central lymphoid organs.
Peripheral: Treg cells & their cytokines downregulate the immune response when pathogen is cleared and help prevent autoimmunity
-some escaped T cells wont recognize MCH-self-Ag and remain immature T cells.
Anergy: state of immunologic tolerance to Ag
On a very basic level, what is the pathophysiology of autoimmune disorders?
result from 1 or more mechanisms producing loss of self-tolerance.
SLE:
- pathogenesis
- what are some drugs that may induce a lupus like syndrome?
SLE:
- many effects are secondary to trapping Ag-Ab complexes in capillaries of visceral structures, also from autoantibody mediated destruction of hose cells.
- estrogen increases Mf proto-oncogene expression and reduces apoptosis in self-reactive b cells.
Lupus like syndrome: procainamide and hydralazine
Rheumatoid Arthritis:
-pathogenesis
Patho: initiated by activation of helper T cells responding to some arthitogenic agent. Target is synovial lining of joints.
Fibrosis, extensive angiogenesis, plasma cells produce abys, mast cells, and mfs are activated, hyperplastic synovial lining around the joint. Marked destruction within the joint,cytokines (IL-1 and TGF-alpha) cause synovial and chondrocyte proliferation. Activated rheumatoid synovium destroys cartilage and tendons, simultaneously osteoclasts and osteoblasts are activated by synovial cytokines destroying the subchondral bone.
RF and IgG form immune complexes that fix complement, attract neutrophiles, and lead to tissue injury.***
Define:
- pannus
- ankylosis
pannus = abnormal layer of fibrovascular tissue or granulation tissue.
Ankylosis: abnormal stiffening and immobility of a joint d/t fusion of the bones.
Scleroderma:
-pathogenesis
Slceroderma:
-diffuse fibrosis of skin and internal organs; autoantibodies that stimulate platelet derived growth factor receptors causing fibroblast dyresgulation.
