Immunology

Question 1

Describe the mechanisms involved in the development and maintenance of tolerance of T and B lymphocytes

Answer 1

Positive and negative selection during maturation to self peptides. Positive selection (life)=weak self antigen recognition, Negative selection (death)=strong self antigen selection. Failure of positive selection (death)=no self recognition

Too much or too little = death
must be just right

Question 2

Describe the role of the thymus and of the AIRE gene in development of T lymphocyte tolerance

Answer 2

Cells in the thymic cortex present peptides derived from self antigens to the developing T lymphocytes to test their recognition and binding affinity.

AutoImmuneREgulator-AIRE gene-codes for a transcription factor express in the thymus. It controls the synthesis of the self peptides used in +/- selection. Mutations in the AIRE gene cause release of self reactive T cells which could result in the development of multiple autoimmune diseases.

Question 3

Identify the mechanisms that have been proposed to be involved in the breaking of immunologic tolerance and induction of autoimmunity

Answer 3

Autoimmune initiation

Genetic susceptibility
Presence of self-reactive lymphocytes
Failure of immunologic tolerance
An immunologic “stimulus”
		Inflammation or Infection

Tolerance broken

Release of sequestered antigen
     Surgical exposure of tissue specific antigens
Imperfect tolerance
     Self-reactive cells present
Drugs and other environmental factors
     Immunosuppressive drugs
Infections
      polyclonal activation (EBV)
      Molecular mimicry/cross reactivity. 
      Cytokine stimulation IFN-gamma
       Induction of Inflammatory response
Genetic mutations/polymorphisms 
     HLA types

mimicry: microb similar to self sequence, and thus host immune defense attacks self instead of the microb.

Question 4

Differentiate organ specific from systemic autoimmune diseases

Answer 4

When self-tolerance is broken and autoimmunity initiated the target Ag dictates the extent of disease; whether systemic or organ specific.

Damage is usually caused by inflammation initiated by Ag-Ab complexes or sensitized T-cells.

Question 5

Discuss the role that gender, genetics, environment and infectious disease play in the development of autoimmune processes

Answer 5

Women seem more predisposed to autoimmune disease than men.
Genetics and environmental risk factors both contribute to autoimmune disease. You may be born with a defective AIRE gene causing all sorts of systemic disease. Additionally lots of x-ray exposure could lead to DNA damage in genes related to immune tolerance.

Question 6

What does CDR stand for and how is it related to TCR, and Ab?

How does the body reconcile unique receptors and the potential for Ab to form against self peptides?

Answer 6

Complementarity determining region/hypervariable region which is on both the heavy and light chains of an Ab, in the variable region, and the VDJ regions of the TCR.

Random recombination of gene segments develop receptors with unique antigen specificity. 
Junctional diversity (add/remove NT)
AB-somatic hypermutation in lymph node after rearrangment

Some of these will bind to self peptides and need to be destroyed through +/- selection events.

Question 7

What’s the difference between central and peripheral tolerance?

Answer 7

Central (+/-) selection

Peripheral- Anergy (no second signal), Deletion, Suppression (T-reg)

Question 8

What’s another name for tolerance and is it heritable?

Answer 8

immunologic unresponsiveness, and no it is not genetically heritable

Question 9

Maintenance of immunologic tolerance is primarily the responsibility of which cell type?

Answer 9

T lymphocytes

Question 10

List the evidence for the autoimmune nature of inflammatory myopathies

Answer 10

Presence of auto-antibodies
Association with HLA types
Increased expression of HLA in muscle
Activated T and B lymphocytes in skeletal muscle
Association with other autoimmune diseases
Thyroid, dermatologic, system lupus erythematosus
Response to immunotherapies

Question 11

List the immune abnormalities which have been identified for :Polymyositis

Answer 11

Proximal muscle weakness

No rash

Presence of CD8+ T cells in muscle biopsy

HLA class I molecules plus co-stimulatory ligands expressed on muscles

CD8 T-cells release perforin and cytokines. Type IV hypersensitivity reaction

Question 12

List the immune abnormalities which have been identified for :Dermatomyositis

Answer 12

Ann inflammatory disease of the muscles accompanied by a skin rash

Characteristic rashes
Antibodies to cell constituents- anti Jo-1

Infiltrating lymphocytes primarily CD4+ and B-cells
HLA molecules over expressed in muscles of

Immune complex deposit and fix complement. Type III hypersensitivity reaction.

Question 13

List the immune abnormalities which have been identified for :Inclusion body myositis

Answer 13

CD8 T-cells release perforin and cytokines. Type IV hypersensitivity

Question 14

Many autoimmune diseases are associated with higher frequency expression of certain HLA molecules

Answer 14

correlation not causation

Question 15

what’s the take home message?

Answer 15

Inflammatory myopathies are autoimmune diseases that present as weakness and/or rash. The autoimmune processes may include autoantibodies or activated CD8+ T cells that activate an inflammatory response in skeletal muscle. Etiologies may include infections, drugs, toxins or other environmental insults.