12. Autoimmunity and tolerance

Question 1

Definitons:
Tolerance
Central tolerance
Peripheral tolerance

Answer 1

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

Question 2

AIRE

Answer 2

Transcription factor in medullary ep. cells that helps negative selection in thymus

Question 3

T cell central tolerance

Answer 3

Negative selection: deletion (Autoreactive T cells -> apoptosis)

Development of Tregs

Question 4

Mechanisms of peripheral T cell tolerance

Answer 4

To prevent potentially autoreactive T cells from reacting to autoantigens.

1. Ignorance (to autoag) - low autoreactive TCR avidity + low conc. of autoag
2. 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…

1. Undergo apoptosis
2. Be suppressed by Tregs
3. Become tolerogenic
4. Become anergic - inability to respond, absence of positive costimulation

Question 5

Cytokines secreted by Tregs

Answer 5

TGFbeta
IL-10

(iummunosuppressive, e.g. against autoreactive T cells)

Question 6

Fate of self-reacting immature B cells

Answer 6

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

Question 7

Which region of BCR an be autoreactive?

Answer 7

V region

Question 8

B1 CD

Answer 8

CD5+

Question 9

Protective role of autoimmunity

Answer 9

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)

Question 10

B1 cells produce

Answer 10

natural autoantibodies

Effects:

• neutralization
• complement lysis of virions
• CR binding -> removal of virus from the circulation
• Ag delivery to secondary lymphatic organs

Question 11

Idiotypic network

Answer 11

Natural autoantibodies connecting together

Question 12

Idiotype

Idiotope

Answer 12

= sum of idiotopes

= variable determinants in a given ab molecule or TCR

Question 13

public idiotope

Answer 13

found on other cells

Question 14

private idiotope

Answer 14

unique for given cell or cell clone

Question 15

Immunological homunculus

Answer 15

Recognition of the most essential autoags of the body by protecting natural autoabs

Question 16

Types of pathological autoimmunity

Answer 16

• autoab + immune complex deposition

- autoreactive T cells

Question 17

Genes involved in suceptibility of autoimmune diseases

Answer 17

1. MHC

2. Genes involved in elimination of autoags. (e.g. costimulatory molecules: CTLA-4, PD..)

Question 18

Factors that may contribute to autoimmune disease development

Answer 18

• 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

Question 19

Epitope spreading

Answer 19

B-cell activated by self-ag/molecular mimickery -> Diversification of T and B cell autoimmunity

Question 20

Superantigen

Answer 20

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

Question 21

Hashimoto’s thyroiditis

Answer 21

CD4 helper cells -> autoreactive B (plasma cells -> necrosis/apoptosis) and Tcyt cells -> apoptosis -> Thyroid cell death -> Hypothyroidism

Question 22

Grave’s disease

Answer 22

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

Question 23

Myasthenia gravis

Answer 23

• Ab inhibits binding of ligand (ACh) to receptor (AChR)
• Antagonisic
• Muscle weakness

Question 24

SLE

Answer 24

• T III HR
• ag: e.g. nucleoproteins (produced anywhere in the body)
• Deposition of immune complexes all over the body