Lecture 15: Immunologic tolerance and autoimmunity

tolerance

Immunological __________ is a lack of response to antigens that is induced by exposure of lymphocytes to these antigens.

central tolerance is establishing tolerance to self antigens when developing lymphocytes encounter these antigens in central (generative/primary) lymphoid organs, while peripheral tolerance occurs when mature lymphocytes encounter self antigens in peripheral tissues

What is the difference between central and peripheral tolerance?

T cell development

1) activation --> proliferation and differentiation

2) tolerance --> anergy vs. apoptosis of lymphocyte

3) ignorance --> no response

What are the three potential consequences when a lymphocyte encounters an antigen?

deletion of developing T cells that recognize self antigen

What is negative selection in the thymus?

not completely understood - three possible factors include:

- the affinity of antigen recognition

- the types of APC presenting to the developing T cell

- availability of certain cytokines

What determines if a T cell will become a regulatory T cell in the thymus?

anergy

A lack of B7-CD28 interaction between T cells and APCs will result in ____________ (activation/anergy)

anergy

Engagement of B7 on APC with CTLA-4 on T cells results in ___________ (activation/anergy)

- upregulation of pro-apoptotic proteins

- engagements of death receptors (FasL and Fas receptor)

What are a couple of mechanisms by which apoptosis of T cells is initiated?

1) its presence in generative (primary/central) lymphoid organs

2) If its presented with secondary signals

3) The persistence of an anitgen

What three features of an antigen may determine if the T cell its presented to becomes tolerant or activated?

tolerogenic self

________________ antigens are typically present in central/primary lymphoid organs (tolerogenic self/immunogenic foreign)

immunogenic foreign

________________ antigens are typically concentrated in peripheral lymphoid organs (tolerogenic self/immunogenic foreign)

tolerogenic self

________________ antigens are typically NOT presented with secondary/co-stimulatory signals (tolerogenic self/immunogenic foreign)

immunogenic foreign

________________ antigens are typically presented with secondary/co-stimulatory signals (tolerogenic self/immunogenic foreign)

tolerogenic self

________________ antigens are typically long-lived (tolerogenic self/immunogenic foreign)

immunogenic foreign

________________ antigens are typically short-lived (tolerogenic self/immunogenic foreign)

deletion of B cells that possess strong recognition of self antigen in the bone marrow OR these B cells will undergo receptor editing to express receptors specific for different antigens

What is negative selection in the context of B cell development?

Mature B lymphocytes that recognize self antigens in peripheral tissues in the absence of specific helper T cells may be rendered functionally unresponsive or die by apoptosis

What does peripheral tolerance in B lymphocytes entail?

thymus

bone marrow

Majority of self-reactive T and B cell clones eliminated in _______ and _______ _______

Th1

T-bet induces the ______ subset of T helper cells

B7

T cells become anergic if encounter antigen presenting cells that do not express ____

IFN-gamma

IL-2

Th1 helper cells produce what major cytokines?

Th2

GATA3 induces the ______ subset of T helper cells

IL-4, 5, 10, & 13

Th2 helper cells produce what major cytokines?

Tregs

FOXP3 induces the ______ subset of T cells

TGF-Beta

IL-10

Treg cells produce what major cytokines?

Th17

ROR-gamma(t) induces the ______ subset of T helper cells

IL-17

Th17 helper cells produce what major cytokine?

defective self-tolerance

abnormal display of self antigens

What are two proposed mechanisms of autoimmunity?

Autoimmune diseases can result from the inadequate elimination or regulation of T or B cells, leading to an imbalance between lymphocyte activation and control.

How can defective self-tolerance lead to autoimmunity?

Self antigens may undergo structural changes due to enzymatic modifications or cellular stress or injury, which can contribute to autoimmunity.

How can abnormal display of self antigens lead to autoimmunity?

molecular mimicry!

how microbes may promote autoimmunity

microbial agents having antigens that mimic host antigens

What is molecular mimicry?

Coxsackie B4 virus, which is similar to glutamic acid decarboxlyase found on pancreatic islet cells - molecular mimicry

What virus has been associated with development of type I diabetes mellitus? Why is this the case?

certain antigens are sequestered during B and T cell development - so these cells can't develop self-tolerance to these antigens ..... then when they're no longer sequestered --> B/T cells react to them

Explain the pathogenesis of autoimmune disease in cases of sequestered antigens

autoantibodies directed against acetylcholine receptors --> block binding of acteylcholine --> blocks excitatory signals for muscle contraction

other antibodies may be directed against muscle specific kinase, which normally functions to cluster acetylcholine receptors into a functional receptor --> blocking this --> no functional receptor formed

What is the underlying mechanism behind myasthenia gravis?

via antibody-dependent cellular cytotoxicity (ADCC)

Other than autoantibodies, what is another mechanism thought to contribute to myasthenia gravis?

Ø Patient's develop autoabs to IgG (rheumatoid factor) which may be IgG, IgA or IgM.

Ø High titers of RF correlate with disease severity. Also T cells that recognize type II collagen and heat shock proteins.

What is the autoimmune mechanism behind rheumatoid arthritis?

Tumor Necrosis Factor

What cytokine is heavily implicated in rheumatoid arthritis?

possible answers:

Ø 1. Collagen type II in FCA

Ø 2. Mycobacterium tuberculosis or adjuvant

arthritis

Ø 3. E. coli and streptococcal cell wall injections.

Ø4. Milk-induced arthritis in rabbits

What are a couple of induced animal models for rheumatoid arthritis in humans?

not fully understood, but genetic and environmental factors seem to play a role... there is failure of self-tolerance against major basic protein --> demyelinating disease

What is the autoimmune mechanism behind multiple sclerosis?

possible answers:

Ø Genetics: MHC class II

Ø Socio-economic status

Ø Women : men 2:1

Ø Pregnancy post partum increased risk

Ø Stress

What are three factors that seem associated with increased risk of developing MS?

possible answers:

Ø Measles virus

Ø Epstein Barr virus

Ø Herpes simplex virus

Ø Varicella zooster virus

Ø Cytomegalovirus

Ø Herpes hominis type-6

Ø Endogenous retrovirus - MS associated retrovirus

name three infectious diseases thought to be associated with development of MS

Visna virus

Canine distemper

Coronovirus

Cornavirus

Herpes simplex

What are a couple of examples of demyelinating viral diseases in animals?

Theiler's Virus

Which virus is known to cause encephalitis/poliomyelitis in the early phase and immune-mediated demyelination in the late phase?

formation of immune complexes against self antigens that deposit in different organs

What is the autoimmune mechanism behind SLE?

C2

40% of patients deficient in what complement factor develop lupus syndrome?

possible answers:

- identical twins

- HLA DRS & DR3

- Def. in C1q, C1r/s, C2

- Polymorphic non-HC genes

What are two genetic factors associated with development of SLE?

desmoglein 3

Pemphigus vulgaris involves IgG autoantibodies against _____________ ____ - a protein found in desmosomes between keratinocytes in the basal layer of the epidermis.