Autoimmunity - Denzin 4/11/16 Flashcards
point of immune regulation
- avoid excessive lymphocyte activation and tissue damage during normal immune responses to pathogens and infections
- prevent inapprop immune responses and rxns specific for self antigens (self-tolerance)
TOLERANCE is a delicate balance between…
- IMMUNITY via activation : T cells (CD4, CD8), B cells, DCs, macrophages
- CONTROL via regulation : Treg, Breg, regulatory DCs, others
immunological self tolerance
specific unresponsiveness to self antigen → individual’s immune system does not attack normal body tissues
therefore…breakdown in self-tolerance → autoimmunity!
recall: types of tolerance
1. central tolerance
- selection of B cells (bone marrow) and T cells (thymus)
- apoptosis
- receptor editing (ex. B cells)
- devpt of Tregs
2. peripheral tolerance
- ignorance
- anergy/fx unresponsiveness [when no costimulation received]
- deletion/apoptosis [mediated by Fas/FasL, triggered by strong self-recognition → increased expression of pro-apop factors]
- suppression [CD4 → Tregs in thymus, Tregs mediate suppression in peripheral tissues]
T cells, selection, and self recognition
- tolerance
- fate of self-recognizing T cells
T cell devpt includes rounds of positive selection and negative selection based on self-affinity (occurs in thymus) via central tolerance
- recall: NEED T cells to be a little self-recognizing, so they can interact with MHC!, but want to keep it under control
post-selection in the thymus, there are still some self-reactive T cells → controlled by peripheral tolerance
fates of T cells that recognize self:
primary fate: apoptosis
also: both in periphery and in thymus, upregulation of FOXP3 → stimulates diff into Treg cells
- inhibit naive T cell activation
- inhibit effector T cell fx
hit T cell fx at every level of maturation!
Treg cells
phenotype
- CD4+
- IL2 receptor HIGH [CD25]
- IL7 receptor LOW [CD127]
- FOXP3+
- GITR+
significance: IPEX (immune dysfx, polyendocrinopathy, enteropathy, X-linked)
- early onset, insulin-dep diabetes (type I)
- severe watery diarrhea
- failure to thrive
- dermatitis
mechanisms of Treg function
therapeutic role???
multiple!
- tons of cytokines (inhibitory and otherwise)
- metabolic disruption (ex. sequestration of IL2, required for T cell survival)
- targeting DCs
therapeutic potential : if we can induce or activate Tregs in immune diseases, might be able to get them under control
-
risks
- Uissues with numbers, specificity, stability
- nonspecific immune suppression, potential to turn into pathogenic T cells themselves (low stability)
Q: how do tissue-specific gene products get expressed in the thymus for T cell selection to take place?
role of autoimmunity
idea: if tissue-specific genes arent being expressed in thymus, youre only going to be able to select for T cells during devpt with a very small (incomplete) subset of proteins
- autoimmunity (APC aka APECED) played a role in answering this Q
APS gene → AIRE (autoimmune regulator)
-
mediates ectopic gene expression in thymus → turns on genes that normally wouldnt be turned on in the thymus → lets the T cell repertoire undergo selection against other proteins
- highlights importance of T cell central tolerance in controlling autoimmunity!
B cells, selection, and Bregs
some self-reactive B cells escape central tolerance mechanisms → have to be controlled by peripheral tolerance
- deletion or anergy [high avidity binding]
- regulation by inhibitory receptors [low avidity binding]
- Breg suppression of B cell responses [v poorly understood]
autoimmunity
- definition
- how it’s caused
relating to/caused by antibodies and/or T cells that attack molecules/cells/organs of tissues producing them
typically arises spontaneously, involving some of the following:
- reduction/loss of Treg activity
- normal self antigens modified by drugs, environmental chemicals, viruses, mutations → look like non-self, and are attacked
- “molecular mimicry” : exposure to antigen that looks v similar to self antigen → leads to activation of self-reactive T cells
2 major patterns of autoimmune disease
1. organ specific autoimmune diseases
-
restricted to a few specific tissues: autoantigens from a few specific organs are recog’d → disease is ltd to these organs
ex. Type 1 DM; Hashimoto’s, Graves; Addison’s; Sjogrens
2. systemic autoimmune diseases
-
involves many tissues/organs: autoantigens are ubiquitous, found everywhere (DNA, cell surface mols, intracellular matrix proteins) → disease affects whole body
ex. rheumatoid arthritis, lupus, scleroderma; often diseases affecting connective tissue or vasculature
genetic basis of autoimmunity
- runs in families
- increased incidence in twins (more in identical ones)
- disease-associated genes exist
-
major association : MHC genes (certain haplotypes have strong assoc with autoimmunity)
- DR2 - multiple sclerosis
- DR1/DR4 - rheumatoid arthritis
- DQ2 - Celiac disease, DM1
-
major association : MHC genes (certain haplotypes have strong assoc with autoimmunity)
multiple genes associated with autoimmunity
- most human autoimmune diseases are multigenic
- single gene defects reveal pathways (ex. AIRE, FOXP3)
most diseases have multiple genes contributing to them
- genome wide assays can link genes to disease
- some genes are implicated in many diseases
- some genes are implicated in only one disease → evidence for distinct mechs of disease
- in most cases, the causative genetic variations have not been identified
what else (besides genetics) affects autoimmunity?
environmental factors
- examples
- NOD mice
genetics cant explain it all!
environmental factors
ex. NOD mouse - DM1
- NOD mice are inbred → most are genetically destined to get DM1
- there’s lots of variability in time of onset and actual pathogenic aspects of onset from investigator to investigatoe → environment must play a role
environmental factors could include drugs, UV rays, other things that lead to some kind of aberrant cell death and release of self antigen → activates autoimmune response
*
what else (besides genetics) caffects autoimmunity?
infection
1. molecular mimicry
immune system responds to a pathogen that somehow has a protein/antigen that LOOKS LIKE SELF ANTIGEN
- activated T cells and antibodies from B cells cross react with self antigens → autoimmunity
ex.
group A streptococcal M protein ~ antigen in cardiac muscle : molecular mimicry might play a role in rheumatic fever
2. bystander activation : infection provides ideal environment for autoimmunity
disruption of cell/tissue barriers can lead to release of sequestered self antigen → activation of non-tolerized cells → autoimmunity
ex. in NOD mice, severity of DM1 is exacerbated by Coxsackie virus
* infection → inflammation, tissue damage, release of sequestered self islet antigen → generation of self-reactive T cells
autoimmunity is far more common in developed world than in undeveloped world
why?
hygiene hypothesis
excessive protection from exposure to dirt/pathogens in early childhood can stunt devpt of immune system
- potentially increased prevalence of asthma and autoimmunity in developed world
- MAYBE…no direct evidence
important to keep in mind bc introduces a caveat to infection/autoimmunity connection:
infection can exacerbate autoimmunity, but some infections can all help prevent autoimmunity!
autoimmune diseases can be triggered by drugs
- immunological response : drug hypersensitivity
- rxn to native form of drug or some metabolite of it complexed with host protein
- usually reversible
- drug-induced autoimmunity
- progresses indep of drug withdrawal
- needs some form of immunosuppressive treatment
ex. Abacavir hypersensitivity syndrome (AHS)
- avacavir is an antiretroviral used to treat HIV → induces a fatal hypersensitivity in patients with a specific HLA
- HLA-B57:01 type ends up putting a protein that wouldnt normally be on the surface out on the surface → induces immune response
