Immune tolerance and privileged sites

Immunogenic Ag

Ag that cause immune response; microbe

Tolerogenic Ag

Ag that induce tolerance; self Ag

What is immunologic tolerance

State of unresponsiveness of immune system to antigen

Process that maintain unresponsiveness to self antigen

Self, central and peripheral tolerance

Self tolerance

Killing of self Ag specific lymphocytes

Central tolerance

Elimination of self reactive T and B cells during maturation in the generative lymphoid organ (negative selection)

Peripheral tolerance

Prevent self reactive mature lymphocytes from attacking self ag

Central T tolerance

Negative selection and Treg generation

AIRE function

Express thymus antigen to train T cell

Mutation of AIRE effect

Negative selection defect → Self reactive T cell live → Autoimmune disease

T cell peripheral tolerance

Treg inhibit self reactive T cell

What is anergy

Self reactive T are unresponsive but not dead → Expression of inhibitory receptors (CTLA4 and PD1)

What is the function of Treg

Suppress activation of self-reactive lymphocytes by either inhibit activation of naive T or inhibit differentiation

Mechanism of Treg

Production of anti-inflammatory cytokine, consume IL2, reduce APC stimulation of T cell

What is the effect of IL2 consumption

Lack of T cell activation

How do Treg reduce ability for APC to stimulate T cell

Express CTLA4

Mutation in CTLA4 effect

No inhibition → No immune regulation → Autoimmune disease

Mutation in CD25 (IL2Ra) effect

No T cell proliferation

Mutation of FOXP3 effect

Def in Treg

Central B tolerance

Receptor editing

Process of receptor editing

Self reactive B cell modify the antigen receptor → Rearrange Ig genes on light chain → Old light chain replaced with new non-reactive chain

Peripheral B cell tolerance

Self-reactive B cell die when enter a tissue → Expression of FcgR2b inhibitory receptor

Mutation in FcgR2b effect

No inhibition signal of B cell

Why aren’t microbiome bacteria destroyed

Treg prevent activation AGAINST response on commensal bacteria

Process of tolerance to commensal bacteria in intestine

Mature lymphocyte recognize but do not react; IL10 producing Treg in infesting; intestinal DC inhibit T cell activation

Tolerance to fetal antigen process

FOXP3 Treg specific to paternal antigen to inhibit immune response; no inflammatory cell in pregnant uterus; poor antigen presentation in placenta; inability to produce Th1; response AGAINST fetal response to baby

What does immunogenic antigen lead to

Cell proliferation

What does tolerogenic antigen lead to

Self reactive cell death

What does nonimmunogenic antigen lead to

No response

Autoimmunity genetic factors

MHC gene or non-MHC gene polymorphism

What is the environmental peripheral tolerance trigger

Cells that bind to self antigen on DC can become self tolerant in resting phase

What is the environmental costimulatory expression trigger

DC express costimulatory signal that bind to self reactive T cell → destruction of self tissue

Molecular mimicry mechanism

Self reactive T cell recognize microbial peptide that happens to look life self antigen → Destruction of self tissue

Process of SLE

Autoantibody form immune complex by binding to antigen in blood → Deposit into blood vessel → Activate complement → Use up complement proteins in process

Process of myasthenia gravis

Autoantibodies produced by B cell → Bind to AChR → Block AChr binding → Muscle weakness

What type of hypersensitivity is myasthenia gravis

Type 2

Grave’s disease/Hashimoto’s thyroiditis process

Autoantibody binding → Decreased thyroid gland function

Rheumatic heart disease process

Cross reactive between streptococcal Ag and human tissue Ag → Molecular mimicry

What are immune privileged tissue

Special immune response in specific organs; no lymphatic drainage or special cells

Where are immune privileged sites

Eye, brain, testis

Characteristic of eye immune response

Blood-eye-barrier;No lymph and blood; a lot of TGF beta; cells express FasL or PD-1L;

Characteristic of brain immune response

BBB; lack of DC; higher threshold for microglia activation

Characteristic of testis immune response

Blood-testis-barrier; sertoli cell lining; A lot of TGF beta; androgens are anti-inflammatory effect on macrophage