Autoimmunity

Question 1

describe autoimmunity

Answer 1

the presence of immune responses against tissue/cells
major cause of morbidity and mortality

can be;
harmless - low titres of auto-antibodies or auto-reactive T cells
harmful - high titres of auto-antibodies or auto-reactive T cells leading to significant tissue/organ damage and chronic inflammation

Question 2

describe how the immune system deals with the presence of auto-reactive T and B cells

Answer 2

specific tolerance mechanisms are required;
deletion of self reactive lymphocytes in primary lymphoid tissues (central tolerance)
inactivation of self-reactive lymphocytes in peripheral tissues that escape central tolerance (peripheral tolerance)
e.g. regulatory T cells

Question 3

describe Treg cells

Answer 3

inactivates lymphocytes
make up 5-10% normal CD4+ T cell population
crucial for suppressing hyper-reactive or auto-reactive T cells (via production of inflammatory cytokines)

Question 4

describe pathogenesis of autoimmune diseases

Answer 4

multi-factorial diseases;
from failure of immunological tolerance - process by which immune system recognises and accepts self-tissue
develops when self-reactive lymphocytes escape from these tolerance mechanisms and become activated

Question 5

describe factors contributing to autoimmune disease

Answer 5

genes
environment (infection, cigarette smoking, hormone levels)
immune regulation (self-tolerance)

Question 6

describe how genes contribute to autoimmune disease

Answer 6

monogenic disorder - single gene defects causing autoimmune disease are rare = IPEX syndrome

most autoimmune diseases result from complex genetic interplay = HLA genes, genes determining sex and other immune responses genes

Question 7

describe IPEX syndrome

Answer 7

immune dysregulation, polyendocrineopathy, enteropathy and X-linked inheritance syndrome (only males affected)

rare genetic disorder of immune dysregulation;
presents early childhood
characterised by overwhelming systemic autoimmunity

mutation in FOXP3 gene - essential for normal development of regulatory T cells
therefore, IPEX is a failure of peripheral tolerance mechanisms due to defective/absent regulatory T cells

Question 8

describe symptoms and treatment for IPEX syndrome

Answer 8

symptoms;
severe infections 
intractable diarrhoea
eczema
very early onset insulin dependant diabetes mellitus
autoimmune maifestations 

treatment;
cure - hematopoietic stem cell transplantation
supportive - immunosuppressive drugs and parental nutrition

Question 9

describe HLA molecules

Answer 9

(MHC molecules)
there are several HLA class I and II genes, each is highly polymorphic 

all nucleated cells express several types of class I molecules on their cell surface;
HLA-A, HLA-B, HLA-C
specialised antigen-presenting cells also express additional class II molecules;
HLA-DR, HLA-DQ, HLA-DP
each individual possess 2 variants of each HLA molecule type

Question 10

describe why HLA molecules display polymorphism

Answer 10

maintenance of diversity in antigen responsiveness at the population level and at the level of the individual;
proteins are processed into many component peptides
different HLA molecules bind to different subsets of peptides
to maximise the net ability to bind all antigenic peptides - multiple different subtypes of HLA molecules, individual HLA molecules exhibit significant allelic diversity

Question 11

describe the influence of HLA molecules in autoimmune disease

Answer 11

predisposing HLA alleles - there is a selective presentation of disease relevant self-peptides by disposing HLA alleles

HLA genes have limited predictive value at present and so are not useful in determining disease risk of individual patients

Question 12

describe sex differences in autoimmune disease

Answer 12

different hormonal influences on lymphocyte function in males and females
alteration of the course of some autoimmune diseases during pregnancy
people with family history
people who are around certain things in the environment
people of certain races or ethnic backgrounds

Question 13

describe potential environmental influences on autoimmune disease mechanisms

Answer 13

altered self-antigens

molecular mimicry - infection; cross-reactivity between antigens expressed by pathogen and self

antigen sequestration - tissues do not communicate with blood or lymph, self-antigens normally sequestered from immune system can become exposed and cause autoimmune reaction during infection/trauma

super-antigens - toxic shock syndrome (staphylococcal proteins, clostridium endotoxin - re-activated auto-reactive T cells that have been inactivated by regulatory T cells)

Question 14

describe classification of autoimmune diseases

Answer 14

1. clinical classification;
   organ specific diseases
   non-organ specific or multi-system autoimmune diseases
2. pathological classification;
   Gel and Coombs (hypersensitivity)

Question 15

describe autoimmune responses mediated by type II hypersensitivity

Answer 15

kidney/lung - Goodpasture’s syndrome (antibodies bind to basement membrane)
endocrine system - Graves’ disease (antibodies bind to TSH receptor)
systemic lupus erythematosus (SLE) (target is nuclear antigens)

Question 16

describe Grave’s disease

Answer 16

Type III hypersensitivity
leading cause of hyperthyroidism
auto-antibodies generated and bind to thyroid stimulating hormone receptor resulting in increased T3 and T4 secretion

Question 17

describe systemic lupus erythematosus

Answer 17

rare type III hypersensitivity, auto-antibodies against nuclear antigens
prototypic multi-system autoimmune disease - skin rashes, nephritis, alveolitis
increased risk of cardiovascular disease
age of onset - 20/30s
high female preponderance
strong genetic predisposition

increased apoptosis, defective clearance of apoptotic material (phagocytosis), loss of tolerance and dysregulation of neutrophil NETs

Question 18

describe autoimmune disease regulated by type IV hypersensitivity

Answer 18

joints - rheumatoid arthitis (self-antigen)
complication - inflammation in lungs and heart)
lung problems include;
fibrosis within lungs (relating to interstitial lung disease)
lung nodules
pleural disease

Question 19

describe Th17 effector cells

Answer 19

highly inflammatory

associated with defence against extracellular bacteria and fungi as the development of autoimmune disease