Immune mediated disease

self tolerance

lack of immune responsiveness to ones own tissue antigens

immunologcal tolerance

when lymphocytes are unresponsive to antigen

mechanisms of tolerance

clonal deletion, clonal anergy, clonal ignorance, regulation

clonal deletion

deletion of self reactive lymphocytes, apoptosis

clonal anergy

silencing of self reactive lymphocytes, clone present but unable to respond

clonal ignorance

self-reactive lymphocytes dont have opportunity to see/respond to antigen, antigen segregation

regulation

active suppression of antigen specific lymphocytes

types of tolerance -where

central and peripheral

central tolerance

central lymphoid organs (thymus and bone marrow), immature lymphocytes that recognise self-antigen are killed or rendered harmlesss

peripheral tolerance

occurs in periphery, tissues and lymph nodes

central T cell tolerance

deletion of self reactive t cells or developemnt of regulatory t cells that go to thymus

t cell education - positive selection

if the TCR has no capacity to bind self MHC molecules, the T cell will die

t cell education - negative selection

if the TCR binds host MHC/peptide complexes present in the thymus too tightly, the T cell will die (remove autoreactive T cells)

t cell education

cells that survive express T cell receptors that have a low affinity for self MHC/peptide complex

central t cell rolerance - thymus

processing and presentation of self antigen present in thymus to immature CD4/CD8 thymocytes

AIRE

autoimmune regulator, transc factors that induces expression of peripheral tissue antigens in the thymus

mutations in the AIRE

give rise to human autoimmune disease, self reactive ly can cause tissue injury unless deleted or supressed

peripheral T cell tolerance

anergy, regulation, deletion

peripheral TCT - anergy

no B7 expressed on APC, T cell inhibitory receptor (CTLA-4) competes w CD28 for B7

T cell activation - signals

recognition of peptide antigen w self MHC, co-stim B7 upregulated, binding and regulated, expressed on APC

periphery TCR - regulation

treg recognise self antigen in thymus, inhibit self reactive that recognise same antigen in the peripherar - cytokines that dampen self respponse, expression of CTLA-4

treg

inhibit activation of t cells that recognise self antigen in periphery, express CD25 and transc factor FoxP3 - inhibit T cell activation

periphery TCT - DELETION

activation induced cell death - apop of mature lymph - coexpression of death receptors Fas and FasL (extrinsic) expression of apoptopic Bcl family, in absence of anti-apoptopic Bcl (intrinsic)

b cell tolerance - no reaction

migrates to periphery and becomes mature B celll

BCT - multivalent (receptor editing)

receptor editing that leads to generation of non-autoreactive mature B cells

BCT - soluble

migrates to periphery, B cell encounters weakly crosslinking antigen of low becomes angeric B cell

BCT - low affintiy, non-x-linking

migrates to periphery, becomes a clonally ignorant mature B cells

BCT - gene rearrangement (MV- RECEPTOR EDITING)

receptor editing - autoreactive b cell rescued by gene erarrwangement, deletion and replacement of self reactive light chain

BCT - multivalent (clonal deletion)

clonal deletion that leads to apoptosis

multivalent

strongly crosslinking antigen in bone marrow

BCT - mulivalent (clonal deleltion) steps

rescue by gene rearrangemnet fails, autoreactive B cell eliminated by apoptosis

b cell tolerance and t cell tolerance

less efficien than T cell tolerance, relies upon efficient T cell help

mechanisms of autoimmunity

inheritance of susceptibilty genes, env triggers that rpomote activation of self reactive lymph

genes that affect immune reg and self tolerance

autoantigen avalibailty and clearance, apoptosis, lymphocyte activation, AIRE

auoimmunity - MHC geneotype

human MHC (HLA) highly polymorpphic, determiens ability of T cells to respond to antibody

autoimmunity - changes to tissue

inflammation, tissue injury, molecular mimicry, drugs and toxins

autoimminity - inflammation

activate anergic autoreactive bystanders (costim), secrete cytokines that impair treg

autoimmunity tissue unjury

tissue antigens altered by injury, cryptic epitopes exposed by injrury

autoimmunity - molecular mimicry

microbial antigens w cross reactivity w autoantigens

autoimmunity - drugs and toxis

bind self antigens so they are recognised as toxins

emerging factors - autoimminity

microbiome (affect relative prop of eff and treg) gender (women) and epitope spreading

autoimmunity - epitope spreading

injury caused by initial autoimmune response exposes previusly concealed self antigens that could be recognised by self reactive lymphocytes

classifications of autoimmune diseases

organ specific, systemic

diabetes

metabolic disorder - hyperglycemia, too much glucose

glucose homeostasis is regulated by

glucose production in liver, lucose uptake and utlisation, action of insulin and glucagon

glucose triggers

insulin release and synthesis, reducing production of glucose in liver

what synthesises insulin

pancreatic beta cells

type i diabetes

absolute insulin deficiency caused by autoimmune destruction of insulin secreting pancreatic beta cells

organ specific autoimmunity - type i diabetes

destruction of pancreatic b cells, failure of self tolerance in t cells, excess t lymphocytes, autoantibodies against b cell antigens

genetic association - type i diabetes

suscepbility locus encoding MHC class II HLA-D, polymorphism in non HLA genes - insulin, CTLA-4, CD25

environmental triggers - type I diabetes

infections, dysbiosis of microbiome

type 2 diabetes

peripheral resistance to the action of insulin coupled w inadequate secretion of insulin