12. Autoimmunity and tolerance Flashcards
Definitons:
Tolerance
Central tolerance
Peripheral tolerance
Tolerance - specific unresponsiveness to the specific antigen
Central tolerance - in central lymphoid organs, unresponsiveness of immature lymphocytes to self, “self reactive” clones are deleted during lymphocyte development
Peripheral tolerance - in mature cells, depends on the sort of antigen and the way of encounter
AIRE
Transcription factor in medullary ep. cells that helps negative selection in thymus
T cell central tolerance
Negative selection: deletion (Autoreactive T cells -> apoptosis)
Development of Tregs
Mechanisms of peripheral T cell tolerance
To prevent potentially autoreactive T cells from reacting to autoantigens.
- Ignorance (to autoag) - low autoreactive TCR avidity + low conc. of autoag
- Immune-priveleged site (e.g. eye, no inflammatory immune response to ag) - supression cytokines and FasL expression on the cells in the site
A potentially autoreactive T cell can…
- Undergo apoptosis
- Be suppressed by Tregs
- Become tolerogenic
- Become anergic - inability to respond, absence of positive costimulation
Cytokines secreted by Tregs
TGFbeta
IL-10
(iummunosuppressive, e.g. against autoreactive T cells)
Fate of self-reacting immature B cells
a. Negative selection: apoptosis (deletion), central
b. Receptor editing: expression of new ag receptor - in the bone marrow, in early stage of B-cell development (VDJ rearrangement - RAG genes are active), central
c. Receptor revision - in germinal centers of secondary lymphoid organs, RAG genes are reactivated, peripheral
d. Anergy (functional unrepsonsiveness) - peripheral
Which region of BCR an be autoreactive?
V region
B1 CD
CD5+
Protective role of autoimmunity
B1 CD5+ cell produces IgM (usually) against:
- Heat shock proteins (CutC, SOD)
- Membrane proteins (beta2m)
- Cytoplasmic proteins (actin)
- Nuclear ags (DNS, histones)
- blood plasma proteins (albumin, IgG)
- cytokines, hormones (IL-1)
B1 cells produce
natural autoantibodies
Effects:
- neutralization
- complement lysis of virions
- CR binding -> removal of virus from the circulation
- Ag delivery to secondary lymphatic organs
Idiotypic network
Natural autoantibodies connecting together
Idiotype
Idiotope
= sum of idiotopes
= variable determinants in a given ab molecule or TCR
public idiotope
found on other cells
private idiotope
unique for given cell or cell clone
Immunological homunculus
Recognition of the most essential autoags of the body by protecting natural autoabs
Types of pathological autoimmunity
- autoab + immune complex deposition
- autoreactive T cells
Genes involved in suceptibility of autoimmune diseases
- MHC
2. Genes involved in elimination of autoags. (e.g. costimulatory molecules: CTLA-4, PD..)
Factors that may contribute to autoimmune disease development
- Drugs and toxins
- Infections: by secretion of inflammatory mediators, by increased costimulation, by the release of tissue ags, by microbial-host cross reactions (molecular mimickery), superantigenic effect
Epitope spreading
B-cell activated by self-ag/molecular mimickery -> Diversification of T and B cell autoimmunity
Superantigen
E.g bacterial toxins
Superantigens bind MHC molecule and TCR from outside of the peptide binding groove -> may induce proliferation of many T cell clones non-specifically
Hashimoto’s thyroiditis
CD4 helper cells -> autoreactive B (plasma cells -> necrosis/apoptosis) and Tcyt cells -> apoptosis -> Thyroid cell death -> Hypothyroidism
Grave’s disease
CD4 T cell -> TSH-reactive B cell -> Plasma cell -> Secretion of TSH abs -> bind to TSHR on Thyroid cells -> Hyperthyroidism
- Type II HR
- Ab stimulates the receptor without ligand (agonistic)
- Overexpression of thyroxine
Myasthenia gravis
- Ab inhibits binding of ligand (ACh) to receptor (AChR)
- Antagonisic
- Muscle weakness
SLE
- T III HR
- ag: e.g. nucleoproteins (produced anywhere in the body)
- Deposition of immune complexes all over the body
