Autoimmunity

Question 1

What is Autoimmunity?

Answer 1

Autoimmunity is immune reactions against self antigens owing to the breakdown of immune tolerance.

Question 2

Do the presence of autoantibodies indicate an autoimmune disease and why?

Answer 2

the mere presence of autoantibodies does not indicate an autoimmune disease exists (autoantibodies in serum of normal individuals or produced after damage to tissues to remove tissue breakdown products).

Question 3

What is Pathologic autoimmunity?

Answer 3

Pathologic autoimmunity is the presence of an immune reaction specific for some self antigen or self tissue, not secondary to tissue damage but is of primary pathogenic significance, with the absence of another well-defined cause of the disease.

Question 4

What is the CLASSIFICATION OF AUTOIMMUNITY?

Answer 4

Organ-specific disease: conditions in which the immune responses are directed against a single organ or tissue. Examples are, Type 1 diabetes mellitus and Grave’s disease.

Systemic or generalized disease: conditions in which the autoimmune reactions are against widespread antigens. Examples are, Systemic lupus erythematosus (SLE).

Question 5

What is Immunologic tolerance?

Answer 5

Immunologic tolerance is the phenomenon of unresponsiveness to an antigen induced by exposure of lymphocytes to that antigen.

Question 6

What is Self-tolerance?

Answer 6

Self-tolerance refers to lack of responsiveness to an individual’s own antigens.

Question 7

How are lymphocytes prevented from recognizing self-antigens?

Answer 7

Because the antigen receptors of lymphocytes are generated by somatic recombination of genes in a random fashion, lymphocytes with receptors capable of recognizing self antigens are generated constantly, and these cells have to be eliminated or inactivated as soon as they recognize self antigens, to prevent them from causing harm.

Question 8

The mechanisms of self-tolerance can be broadly classified into two groups:

Answer 8

1. central tolerance
2. peripheral tolerance.

Question 9

What is Central tolerance?

Answer 9

Central tolerance; In this process, immature self-reactive T and B lymphocyte that recognize self antigens during their maturation in the central (or generative) lymphoid organs (the thymus for T cells and the bone marrow for B cells) are killed or rendered harmless.

Question 10

Describe Central tolerance in T cells (how does it occur & what protein is involved)

Answer 10

Central tolerance in T cells;
Negative selection or deletion (death by apoptosis), is responsible for eliminating self-reactive lymphocytes from the T-cell pool. A protein called AIRE (autoimmune regulator) is critical for deletion of immature T cells.

In the CD4+ T-cell lineage, some of the cells that see self antigens in the thymus do not die but develop into regulatory T cell

Question 11

Discuss Central tolerance in B cells

Answer 11

Central tolerance in B cells;
Receptor editing where many of the cells reactivate the machinery of antigen receptor gene rearrangement and begin to express new antigen receptors, not specific for self antigens (after recognition of self antigen in the bone marrow).

Self reactive cells undergo apoptosis (if receptor editing does not occur), thus purging potentially dangerous lymphocytes from the mature pool.

Question 12

What is Peripheral tolerance and the mechanisms involved?

Answer 12

Peripheral tolerance; Self-reactive lymphocytes that escape negative selection can inflict tissue injury unless they are deleted or muzzled in the peripheral tissues. Several mechanisms silence potentially autoreactive T and B cells in peripheral tissues.

They are;
Anergy
Suppression by regulatory T cells
Deletion by apoptosis

Question 13

What is Anergy?

Answer 13

Anergy: a phenomenon whereby lymphocytes that recognize self antigens may be rendered functionally unresponsive.

Question 14

The activation of antigen-specific T cells requires which two signals?

Answer 14

recognition of peptide antigen in association with self MHC molecules on the surface of APCs
a set of costimulatory signals (“second signals”) from APCs.

Question 15

Discuss the second signal (from the APC) required to activate T cells

Answer 15

These second signals are provided by CD28 (T cell-associated molecule), that bind to their ligands (the costimulators B7-1 and B7-2) on APCs.

If the antigen is presented to T cells without adequate levels of costimulators, the cells become anergic.

In normal tissues, costimulatory molecules are not expressed or are weakly expressed on APCs. Thus an encounter between autoreactive T cells and their specific self antigens displayed by these APCs may lead to anergy.

Question 16

What happens to B-cells in peripheral tissues?

Answer 16

In peripheral tissues, the B cells become unable to respond to subsequent antigenic stimulation and may be excluded from lymphoid follicles, resulting in their death.

Question 17

What happens when B lymphocytes express inhibitory receptors?

Answer 17

B lymphocytes also express inhibitory receptors that may play a role in limiting their activation and preventing responses to if B cells encounter self antigen.

Question 18

Discuss is lymphocyte Suppression by regulatory T cells

Also discuss Mutations in FOXP3

Answer 18

Suppression by regulatory T cells: A population of T cells which functions to prevent immune reactions against self antigens.
The best defined regulatory T cells are CD4+ cells that express high levels of CD25, the α chain of the IL-2 receptor, and a transcription factor of the forkhead family, called FOXP3.
Both IL-2 and FOXP3 are required for the development and maintenance of functional CD4+ regulatory T cells.

Mutations in FOXP3 result in severe autoimmunity in humans; these mutations are the cause of a systemic autoimmune disease called IPEX (an acronym for Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked).
The inhibitory activity of regulatory T cells may be mediated in part by the secretion of immunosuppressive cytokines such as IL-10 and TGF-β, which inhibit lymphocyte activation and effector functions.
Regulatory T cells also express CTLA-4, which may bind to B7 molecules on APCs and reduce their ability to activate T cells via CD28.

Question 19

Discuss autoreactive lymphocyte Deletion by apoptosis

Answer 19

Deletion by apoptosis: T cells that recognize self antigens may receive signals that promote their death by apoptosis.
It is postulated that if T cells recognize self antigens, they may express a pro-apoptotic member of the Bcl family, called Bim, without antiapoptotic members of the family like Bcl-2 and Bcl-x.
Unopposed Bim triggers apoptosis by the mitochondrial pathway.

Question 20

What is the Fas-Fas ligand system?
What is the condition called if there is a mutation in the system?

Answer 20

• The death receptor Fas (CD95) is expressed on lymphocytes as well as many other cells, whereas the Fas ligand (FasL) is expressed mainly on activated T lymphocytes.
• The engagement of Fas by FasL induces apoptosis of activated T cells.
• It is postulated that if self antigens engage antigen receptors of self-reactive T cells, Fas and FasL are co-expressed, leading to elimination of the cells via Fas mediated apoptosis
• Self-reactive B cells may also be deleted by FasL on T cells engaging Fas on the B cells.
• Mutation in the Fas gene in humans is the autoimmune lymphoproliferative syndrome (ALPS).

Question 21

What is the underlying cause of autoimmune diseases?
How does it arise?

Answer 21

The underlying cause of autoimmune diseases is the failure of tolerance, which allows responses to develop against self antigens.

Autoimmunity arises from a combination of the inheritance of susceptibility genes, which may contribute to the breakdown of self-tolerance, and environmental triggers, such as infections and tissue damage, which promote the activation of self-reactive lymphocytes

Question 22

susceptibility genes and environmental triggers induce a number of changes that contribute to the development of autoimmunity, which are?

Answer 22

susceptibility genes and environmental triggers induce a number of changes that contribute to the development of autoimmunity:

Defective tolerance or regulation:

There is a failure of the mechanisms that maintain self-tolerance, which is fundamental to the development of autoimmune diseases.

Abnormal display of self antigens:

There is increased expression and persistence of self antigens that are normally cleared, or structural changes in these antigens due to enzymatic modifications or from cellular stress or injury ( leading to display of antigenic epitopes that are not normally expressed).

Inflammation or an initial innate immune response:

The innate immune response is a strong stimulus for the subsequent activation of lymphocytes and the generation of adaptive immune responses. Microbes or cell injury may elicit local inflammatory reactions resembling innate immune responses, and these may be critical inducers of the autoimmune disease

Question 23

What is the role of Susceptibility Genes?

Answer 23

Role of Susceptibility Genes
Most autoimmune diseases are complex multigenic disorders.
The incidence of many autoimmune diseases is greater in twins of affected individuals than in the general population.
And greater in monozygotic than in dizygotic twins, proof that genetics contributes to the development of these disorder

Question 24

What is the Association of HLA Alleles with Disease?

Answer 24

Among the genes known to be associated with autoimmunity, the greatest contribution is that of HLA genes.
The most striking of these associations is between ankylosing spondylitis and HLA-B27.
Individuals who inherit this class I HLA allele have a 100-200 fold greater chance of developing the disease compared with those who do not carry HLA-B27.
Many autoimmune diseases are associated with different class II HLA alleles.

It is also important to understand that different HLA alleles may contribute to a disease but their presence is not, by itself, the cause of any disease. Thus, vast majority of individuals who inherit HLA-B27 allele never develop ankylosing spondylitis.

Question 25

What is the Association of Non-MHC Genes with Autoimmune Diseases?

Answer 25

multiple non-MHC genes are associated with various autoimmune diseases.
Some of these genes are disease-specific, but many of the associations are seen in multiple disorders
This suggests that the products of these genes affect general mechanisms of immune regulation and self-tolerance.

Question 26

What are the 2 effects of infections in an autoimmune disease?

What is molecular mimicry and give an example?

Answer 26

Autoimmune reactions may be triggered by infections.

Two mechanisms have been postulated to explain the link between infections and autoimmunity.

First, infections may upregulate the expression of costimulators on APCs.

If these cells are presenting self antigens, the result may be a breakdown of anergy and activation of T cells specific for the self antigens.

Second, some microbes may express antigens that have the same amino acid sequences as self antigens. Immune responses against the microbial antigens may result in the activation of self-reactive lymphocytes. This phenomenon is called molecular mimicry.

A clear example of such mimicry is rheumatic heart disease, in which antibodies against streptococcal proteins cross-react with myocardial proteins and cause myocarditis.

Question 27

What are the GENERAL FEATURES OF AUTOIMMUNE DISEASES?

Answer 27

1. Autoimmune diseases tend to be chronic, sometimes with relapses and remissions, and the damage is often progressive.

• One reason for the chronicity is that the immune system contains many intrinsic amplification loops that allow small numbers of antigen-specific lymphocytes to accomplish their task of eradicating complex infections.

• When the response is inappropriately directed against self tissues, the same amplification mechanisms exacerbate and prolong the injury.

• Another reason for the persistence and progression of autoimmune disease is the phenomenon of epitope spreading, in which an immune response against one self antigen causes tissue damage, releasing other antigens, and resulting in the activation of lymphocytes by these newly encountered epitopes.

2. The clinical and pathologic manifestations of an autoimmune disease are determined by the nature of the underlying immune response.
3. Some of these diseases are caused by autoantibodies, whose formation may be associated with dysregulated germinal centre reactions.
4. Most chronic inflammatory diseases are caused by abnormal and excessive TH1 and TH17 responses; examples include psoriasis, multiple sclerosis.
5. CD8+ CTLs contribute to killing of cells, such as islet βcells in type 1 diabetes.
6. In some autoimmune diseases, (rheumatoid arthritis), both antibodies and T cell–mediated inflammation may be involved.

Answer 28

The clinical and pathologic manifestations of an autoimmune disease are determined by the nature of the underlying immune response.
Some of these diseases are caused by autoantibodies, whose formation may be associated with dysregulated germinal centre reactions.
Most chronic inflammatory diseases are caused by abnormal and excessive TH1 and TH17 responses; examples include psoriasis, multiple sclerosis.
CD8+ CTLs contribute to killing of cells, such as islet βcells in type 1 diabetes.
In some autoimmune diseases, (rheumatoid arthritis), both antibodies and T cell–mediated inflammation may be involved.

Question 29

Examples of SYSTEMIC AUTOIMMUNE DISEASES?

Answer 29

Diseases Mediated by antibodies;
Systemic Lupus Erythematosus (SLE)

Diseases Mediated by T cells:
Rheumatoid arthritis
Sjögren Syndrome
Systemic Sclerosis (Scleroderma)

Question 30

Examples of Organ-specific AUTOIMMUNE DISEASES?

Answer 30

Diseases mediated by antibodies:

Autoimmune hemolytic anemia
Autoimmune thrombocytopenia
Gastritis of pernicious anemia
graves disease
myasthenia gravis
good pasture syndrome

Diseases mediated by T cells:
Type one diabetes
multiple sclerosis

Question 31

What is SLE?

Answer 31

Systemic Lupus Erythematosus (SLE) is an autoimmune disease involving multiple organs, characterized by a the production of autoantibodies, particularly antinuclear antibodies (ANAs), in which injury is caused mainly by deposition of immune complexes and binding of antibodies to various cells and tissues
A type III hypersensitivity

Question 32

What are the spectrum of autoantibodies in SLE?

Answer 32

(1) antibodies to DNA
(2) antibodies to histones,
(3) antibodies to nonhistone proteins bound to RNA, and
(4) antibodies to nucleolar antigens

Question 32

Which of the autoantibodies strongly suggest SLE?

Answer 32

anti-smith antigen

Question 32

Mention other antibodies produced by SLE
patients and mention the element they are directed against.

Answer 32

Antibodies against…
1. Double-stranded DNA (anti-dsDNA) (40-60%)

Non-histone proteins bound to RNA
2. U1-RNP (30-40%)
3. Smith (Sm) antigen (20-30%)
4. Ro (SS-A)/La (SS-B) nucleoproteins (30-50%)

5. Phospholipid-protein complexes (anti-PL) (30-40%)
   6.Multiple nuclear antigens (“generic ANAs”) (95-100%)

Question 32

Mention the 3 factors involved in the etiology and pathogenesis of SLE

Answer 32

1. Genetic factors (family members of patients have an increased risk of developing SLE)
2. Immunologic factors (e.g. failure of self-tolerance in B cells)
3. Environmental factors (Exposure to ultraviolet (UV) light exacerbates the
   disease in many individuals)

Question 33

Although any organs can be involved. Mention the most characteristic tissues affected in SLE

Answer 33

The most characteristic lesions result from immune complex deposition in blood vessels, kidneys, connective tissue, and skin.

Question 34

Discuss the Organ changes in SLE

Question 35

List the clinical featuresofSLE

Answer 35

1. a butterfly rash over the face, fever, pain but no deformity in one or more peripheral joints (feet, ankles, knees, hips, fingers, wrists, elbows, shoulders)
2. pleuritic chest pain
3. and photosensitivity