Autoimmunity

Question 1

definition Autoimmunity

Answer 1

breakdown of the immune system’s ability to differentiate between “self and non-self”

Question 2

definition Autoimmune disease

Answer 2

Immunoglobulins (autoantibodies, B-lymphocytes activation) or cytotoxic T-lymphocytes display specificity self-antigens autoantigens and give rise to the pathogenesis of the disease

Question 3

what is tolerance

Answer 3

Tolerance is specific immunologic unresponsiveness, i.e., an immune response to a certain antigen does not occur, although the immune system is otherwise functioning normally.

Question 4

what is Self reactive T cell

Answer 4

-immune cell that recognize and attack the body’s own tissue.
-In a healthy immune system, self-reactive cells are eliminated or suppressed to prevent them from attacking self-tissues. However, in autoimmune diseases, this self-tolerance mechanism fails, leading to the activation of self-reactive cells and subsequent tissue damage

In general, antigens that are present during embryonic life are considered “self” and do not stimulate an immunologic response, i.e., we are tolerant to those antigens.
The lack of an immune response is caused by the deletion of self-reactive T-cell precursors in the foetal thymus.

Question 5

T cell tolerance

Answer 5

The main process by which T lymphocytes acquire the ability to distinguish “self” from “nonself” occurs in the foetal thymus. This process, called clonal deletion involves the killing of T cells (“negative selection”) that react against antigens (primarily self MHC proteins) present in the foetus at that time.

The self-reactive cells die by a process of programmed cell death called apoptosis.

Question 6

T cell tolerance in thymus called?

Answer 6

Tolerance to self acquired within the thymus is called central tolerance, whereas tolerance acquired outside the thymus is called peripheral tolerance.

Question 7

•The most important step in the production of autoimmune disease is …

Answer 7

•The most important step in the production of autoimmune disease is the activation of self-reactive helper (CD4) T cells.
• These self-reactive Th-1 or Th-2 cells can induce either cell- mediated or antibody-mediated autoimmune reactions, respectively.

Question 8

Factors responsible for triggering of autoimmune diseases

Answer 8

Factors responsible for triggering of autoimmune diseases
• Genetic
• Hormonal
• Environmental

Question 9

genetic factors

Answer 9

genetic predisposition to these disorders.
•There is a strong association of some diseases with certain human leukocyte antigen (HLA) specificities, especially the class II genes. For example, rheumatoid arthritis occurs predominantly in individuals carrying the HLA-DR4 gene.
•Ankylosing spondylitis is 100 times more likely to occur in people who carry HLA-B27, a class I gene, than in those who do not carry that gene.

Question 10

Hormonal Factors

Answer 10

Approximately 90% of all autoimmune diseases occur in women. Although the explanation for this markedly unequal gender ratio is unclear, there is some evidence from animal models that oestrogen can alter the B-cell repertoire and enhance the formation of antibody to DNA.
•Clinically, the observation that systemic lupus erythematosus either appears or exacerbates during pregnancy (or immediately postpartum) supports the idea that hormones play an important role in predisposing women to autoimmune diseases.

Question 11

environmental factors

Answer 11

There are several environmental agents that trigger autoimmune diseases, most of which are either bacteria or viruses.
•For example, pharyngitis caused by Streptococcus pyogenes predisposes to rheumatic fever.
•Though it is speculative at this time, but members of the normal flora of the bowel are thought to play a role in the genesis of inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis.

Question 12

Mechanisms autoimmune

Answer 12

• Molecular mimicry
• Alteration of normal proteins
• Release of sequestered antigens
• Failure of regulatory T cells

Question 13

Mechanisms – Molecular mimicry

Answer 13

Mechanisms – Molecular mimicry
• Various bacteria and viruses are implicated as the source of cross- reacting antigens that trigger the activation of autoreactive T cells or B cells.
•The concept of molecular mimicry is used to explain these phenomena, i.e., the environmental trigger resembles (mimics) a component of the body sufficiently that an immune attack is directed against the cross-reacting body component
•One of the best-characterized examples of molecular mimicry is the relationship between the M protein of S. pyogenes and the myosin of cardiac muscle. Antibodies against certain M proteins cross-react with cardiac myosin, leading to rheumatic fever

Question 14

Mechanisms – Alteration of normal proteins

Answer 14

Drugs can bind to normal proteins and make them immunogenic. Procainamide-induced systemic lupus erythematosus is an example of this mechanism.

Question 15

Mechanisms – Release of sequestered antigens

Answer 15

•Certain tissues, e.g., sperm, central nervous system, and the lens and uveal tract of the eye, are sequestered so that their antigens are not exposed to the immune system.
• These are known as immunologically privileged sites.
• When such antigens enter the circulation accidentally, e.g., after damage, they elicit both humoral and cellular responses, producing aspermatogenesis, encephalitis, or endophthalmitis, respectively.

Question 16

Mechanisms – Failure of Regulatory T cells

Answer 16

• Regulatory T cells (Tregs) suppress the proinflammatory effects of other T cells.
•An important function of Treg cells is to produce IL-10, which inhibits proinflammatoryTh-1 cells.
•If Treg cells fail, then autoimmune diseases characterized by inflammation such as systemic lupus erythematous, can occur.

Question 17

Multiple Sclerosis

Answer 17

• It is an inflammatory, T-cell–mediated autoimmune disease characterized by the demyelination or destruction of the myelin sheaths surrounding central nervous system nerve axons.
• It is caused by the release of sequestered myelin antigens following trauma to the CNS, or molecular mimicry to a neuroepitope following a viral infection. EBV is one of many viruses that have been implicated in MS.

Question 18

multiple sclerosis clinical findings and treatment

Answer 18

•The clinical findings in multiple sclerosis typically wax and wane and affect both sensory and motor functions. MRI of the brain reveals plaques in the white matter.
• Immunosuppressive drugs, e.g., prednisone, methotrexate, or beta interferon, are effective in reducing the severity of some of the symptoms.

Question 19

Hashimoto’s Thyroiditis

Answer 19

• This disease, most commonly found in middle-aged women, is characterized by the production of antibodies to two major thyroid proteins, thyroid peroxidase and the hormone thyroglobulin.
•These autoantibodies play a major role in the destruction of the thyroid gland, eventually causing a decline in the output of thyroid hormones resulting in hypothyroidism.

Question 20

Autoimmune Haemolytic Anaemia

Answer 20

• In autoimmune hemolytic anemia, antibodies specific for blood group antigens (including Rh) expressed on the surface of RBCs are responsible for destroying these RBCs. This results in anaemia, a reduced number of RBCs or decreased haemoglobin level in the circulation.
• Mechanisms include
• activation of complement cascade and eventual lysis of RBC
• opsonization of RBC facilitated by antibodies and C3b, leading to engulfment by macrophages
•Destruction of RBCs by antibody-dependent cellular cytotoxicity (ADCC)

Question 21

Idiopathic Thrombocytopenic Pupura

Answer 21

Idiopathic thrombocytopenic purpura(ITP) is caused by antibodies directed against platelets. Platelets coated with antibody are either destroyed in the spleen or lysed by the membrane attack complex of complement

Question 22

Myasthenia Gravis

Answer 22

•The target self-antigen in this disease is the acetylcholine
receptor at neuromuscular junctions.
•The autoantibody acts as an antagonist that blocks the
binding of acetylcholine (ACh) to the receptor.
•This inhibits the nerve impulse from being transmitted across the neuromuscular junction, resulting in severe muscle weakness, manifested by difficulty in chewing, swallowing, and breathing and eventually death from respiratory failure.

Question 23

who can get myasthenia gravis

Answer 23

Myasthenia gravis may affect individuals of any age, but the peak incidence occurs in women in their late-20s and men in their 50s and 60s

Question 24

Insulin Dependent Diabetes Mellitus (IDDM)

Answer 24

n this disease, autoreactive T cells destroy the islet cells of the pancreas. The main antigen against which the T-cell attack is directed is the islet cell enzyme, glutamic acid decarboxylase. Infection with Coxsackie virus B4 has been shown to be a trigger of IDDM in mice, but it is yet to be established as a cause in human diabetes.
•There is a six–amino acid sequence in common between a Coxsackie virus protein and glutamic acid decarboxylase. Antibodies against various antigens of the beta islet cells also are produced, but the major damage is T-cell mediated.

Question 25

Grave’s Disease

Answer 25

•Patients with this disease develop autoantibodies against receptors for thyroid-stimulating hormone (TSH) that are expressed on the surface of thyroid cells.
•The interaction of autoantibodies with the TSH receptor activates the cell in a manner similar to TSH activation, thereby stimulating excess production of thyroid hormone leading to hyperthyroidism.

Question 26

who commonly get graves’ disease

Answer 26

• It most commonly affects women in their 30s and 40s; the female to male ratio is about 8:1.

Question 27

Guillain-Barre Syndrome (GBS)

Answer 27

• This disease is the most common cause of acute paralysis.
•It follows a variety of infectious diseases such as viral illnesses (e.g., upper respiratory tract infections, HIV infection, and mononucleosis caused by Epstein-Barr virus, cytomegalovirus and zika virus) and diarrhoea caused by Campylobacter jejuni

Question 28

symptoms and treatment GBS

Answer 28

•Antibodies against myelin protein are formed and result
•The main symptoms are those of a rapidly progressing ascending paralysis.
•The treatment involves either intravenous immunoglobulins or plasmapheresis.
in a demyelinating polyneuropathy.

Question 29

Systemic Lupus Erythematosus (SLE)

Answer 29

In this disease, autoantibodies are formed against DNA, histones, nucleolar proteins, and other components of the cell nucleus. Antibodies against double-stranded DNA are the hallmark of systemic lupus erythematosus.
• The disease affects primarily women between the ages of 20 and 60 years.
•Individuals with HLA-DR2 or -DR3 genes are predisposed to SLE. The agent that induces these autoantibodies in most patients is unknown. However, two drugs, procainamide and hydralazine, are known to cause SLE.

Question 30

Rheumatoid Arthritis

Answer 30

•In this disease, autoantibodies are formed against IgG. These autoantibodies are called rheumatoid factors and are of the IgM class.
• Rheumatoid arthritis affects primarily women between the ages of 30 and 50 years.
• People with HLA-DR4 genes are predisposed to rheumatoid arthritis.
• The agent that induces these autoantibodies is unknown.
• Within the inflamed joints, the synovial membrane is infiltrated with T cells, plasma cells, and macrophages, and the synovial fluid contains high levels of macrophage-produced inflammatory cytokines such as tumor necrosis factor (TNF), IL-1, and IL-8.

Question 31

Rheumatic Fever

Answer 31

•Group A streptococcal infections regularly precede the development of rheumatic fever.
• Antibodies against the M protein of group A streptococci that cross-react with myosin in cardiac muscle and proteins in joint and brain tissue are involved in the pathogenesis of rheumatic fever.

Question 32

Goodpasture’s Syndrome

Answer 32

In this syndrome, autoantibodies are formed against the collagen in basement membranes of the kidneys and lungs.
• Goodpasture’s syndrome affects primarily young men, and those with HLA-DR2 genes are at risk for this disease.
•The agent that induces these autoantibodies is unknown, but GS often follows a viral infection.

Question 33

Laboratory Diagnosis of autoimmune diseases

Answer 33

• Routine investigations – Urine examination – renal pathology, proteinuria, haematuria, urine sediments
• Haematological investigations – Hb, RBC, WBC counts, Platelet counts, ESR (inflammatory process)
• Biochemical tests – Renal function tests, liver enzymes • Serological tests - CRP, Rheumatoid factor, Antinuclear
antibody, ASO titre, Immunofluorescence
• Study of HLA association

Question 34

Treatment of autoimmune diseas

Answer 34

• The conceptual basis for the treatment of autoimmune diseases is to reduce the patient’s immune response sufficiently to eliminate the symptoms.
•Corticosteroids, such as prednisone, are the mainstay of treatment, to which antimetabolites, such as azathioprine and methotrexate, can be added.
• Immunosuppressive therapy must be given cautiously because of the risk of opportunistic infections.
• Anticytokine therapies have proven very successful against several autoimmune diseases. Blockade of TNF-α by monoclonal antibody or soluble receptor is an important therapeutic option in RA and inflammatory bowel disease.