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Author : Dr.

Saurav K Sarkar Designation : Lecturer


Discipline : B. Tech (Biotech) Module : BT 501 Semester : VI
Topic : Autoimmunity

An autoimmune disease is a pathologic condition caused by an autoimmune response.


Autoimmune diseases can be caused by antibodies or T cells and form a spectrum between (a) organ-specific
diseases, where immune responses are directed to an antigen unique to a single organ or gland and the
disease manifestations are usually confined to that organ or gland or cell type (e.g. Hashimoto's disease or
thyroiditis and pernicious anemia) and (b) systemic autoimmune diseases, where immune response is
directed toward a broad range of antigens (e.g. SLE) where lesions and tissue damage are widespread.
Systemic autoimmune diseases are usually due to defective immune regulation that results in hyperactive T
and B cells. In the intermediate range of the spectrum, the lesion tends to be localized to one or two organs
(e.g. Goodpasture's disease where auto-Abs are deposited on the basement membrane of both kidney
glomeruli and lung parenchyma, causing the chronic glomerulonephritis and pulmonary hemorrhages).
Human Autoimmune Diseases
Extent
Disease Autoantigen Symptoms
*
Type II: antibodies to cell surface molecules
Lysis of RBC by
Rh blood group antigens, I
Autoimmune hemolytic anemia complement and FcR+ cells, O
antigen
anemia
Autoimmune thrombocytopenic
Platelet integrin GpIIb:IIIa Abnormal bleeding O
purpura
Basement membrane Type IVGlomerulonephritis,
Goodpasture's syndrome O
collagen pulmonary hemorrhage
Thyroid-stimulating hormone
Graves' disease Thyroid over-activity O
receptor
Thyroglobulin, thyroid
Hashimoto's thyroiditis Thyroid under-activity O
peroxidase
Hypoglycemia Insulin receptor (agonist) Low blood glucose O
High blood glucose,
Insulin-resistant diabetes Insulin receptor (antagonist) O
ketoacidosis
 chain of nicotinic
Myasthenia gravis Progressive weakness O
acetylcholine receptor
Pemphigus vulgaris Epidermal cadherin Skin blisters O
Intrinsic factor, gastric parietal
Pernicious anemia Anemia O
cells
Streptococcal cell wall antigens;
Arthritis, myocarditis, heart
Rheumatic fever antibodies cross-react with O
valve scars
heart muscle
Spontaneous infertility Sperm antigens Infertility O
Type III: Immune complex disease
Ankylosing spondylitis Immune complexes Damage to vertebrae S
Mixed essentialRheumatoid factor IgG
Systemic vasculitis S
cryoglobulinemia complexes
Rheumatoid factor IgG
Rheumatoid arthritis Arthritis S
complexes
Systemic lupus erythematosusDNA, histones, ribosomes,Glomerulonephritis,
S
(SLE) snRNP, scRNP vasculitis, rash
Type IV: T cell-mediated disease
Experimental autoimmuneMyelin basic protein,
Brain invasion by CD4 T
encephalomyelitis (EAE),proteolipid protein, myelin S
cells, weakness
multiple sclerosis (MS) oligodendrocyte glycoprotein
Hashimoto's thyroiditis Thyroid antigen(s) Thyroid under-activity O
Insulin-dependent (Type I)
Pancreatic  cell antigen(s)  cell destruction O
diabetes mellitus (IDDM)
Joint inflammation and
Rheumatoid arthritis Unknown synovial joint antigen S
destruction
*O = organ-specific, S = systemic

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Author : Dr. Saurav K Sarkar Designation : Lecturer
Discipline : B. Tech (Biotech) Module : BT 501 Semester : VI
Topic : Autoimmunity

Autoimmune diseases are initiated by activation of antigen-specific T cells and cell mediated immunity is
particularly impaired, causing lymphocytopenia as in SLE and other disorders. TH2 cells activate B cells to
make autoantibodies, which (by activating complement) damage tissues directly or initiate prolonged
inflammation. CTL and macrophages activated by TH1 cells are directly cytotoxic and also promote
inflammation. The events that initiate specific autoimmune diseases are not known. However, patients with
systemic autoimmune diseases despite having high levels of Ig respond poorly when immunized with
exogenous Ag, as if their whole immune system were preoccupied with responses to self-Ag.

Disease concordance

Studies of IDDM, rheumatoid arthritis, MS, and SLE in identical twins generally show a 20% in disease
concordance, i.e. in 20% of cases where one twin develops autoimmunity, the other will develop the same
disease. In fraternal twins, concordance is 5%. This indicates that genetic background is an important but not
the only risk factor. Sex hormones are linked with the occurrence of some autoimmune disease: women are
10-20 times more likely than men to develop multiple sclerosis or SLE, while men are 3 times more likely
than women to develop ankylosing spondylitis. Other autoimmune diseases such as IDDM, myasthenia
gravis and Goodpasture's syndrome occur with equal incidence in both men and women.

Determinant spreading

As cells are killed and their contents are released more antigens, many of which are not normally present
outside of cells to induce clonal deletion or clonal anergy, become available to activate the immune system.
This is determinant spreading. Activation of an autoimmune T cells specific for one epitope can activate B
cells specific for several different epitopes associated with the same multimolecular complex. In Systemic
Lupus Erythematosis (SLE), a TH cell specific for H1 histone can activate both H1 specific and DNA specific B
cells. Both types of B cells bind nucleosomes and present H1 peptides to TH cells.

Thyroiditis

This is also known as Hashimoto's disease. Patients suffer from chronic inflammation of the thyroid gland.
Gradual destruction of the secretory cells and loss of thyroid function occur, followed by hypothyroidism.
Serum of patients contain high level of anti-thyroglobulin Abs. Approximately 0.010.05  µg/ml thyroid
autoantigen thyroglobulin (Tg) normally reaches the serum, and such a low concentration produces low-zone
tolerance. So, anti self-Tg B cells, even if present, are non resposive to self-Tg due to lack of cooperation from
tolerant T cells. If now a foreign or new antigenic determinant appears on Tg due to some modification, then
it will stimulate a different set of TH cells specific for the new determinant. These TH cells can then cooperate
with the existing, quiescent anti-Tg B cells allowing them to secrete anti-Tg Abs.

Rabbits injected with chemically modified rabbit Tg, or with cross-reacting hog Tg, develop thyroiditis, with
production of Ab to native rabbit Tg.

Pernicious Anemia

in this autoimmune disease, defective red cell maturation is prevalent due to non-absorption and lack of
vitamin Big . Intrinsic factor (InF) is a protein moiety, secreted by parietal cells of the gastric mucosa and is
responsible for the absorption of vitamin 812- In pernicious anemia patients, auto-Abs to InF prevail and
thus inactivate it. Most patients with the disease have Abs to parietal cells, as revealed by
immunofluorescence of gastric biopsies. Cell-mediated immunity to these cells could also be present.

It was demonstrated that when InF, vitamin B^ and the serum from a patient with this disease are orally
administered, the serum was found to prevent InF from mediating the absorption of vitamin bi? into the
body; further studies showed the active principle in the serum to be an antibody. Auto-Abs being in the
serum of the patient do not seem to be effective in neutralizing the physiological activity of InF; human

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Author : Dr. Saurav K Sarkar Designation : Lecturer
Discipline : B. Tech (Biotech) Module : BT 501 Semester : VI
Topic : Autoimmunity

volunteers immunized with hog InF in complete Freunds adjuvant had high serum Ab levels and intense
delayed-type hypersensitivity to fnF but still absorbed vitamin 612 well when fed with hog InF, These
observations imply that the auto-Abs to InF have Jo be present within the lurnen of the gastrointestinal tract
to be biologically effective. These auto-Abs, produced by plasma cells in the gastric mucosa, are able to
function within the stomach {normally with extreme acidic condition); atrophy of the affected mucosa
reduces the secretion of HCL in the stomach. Thus, by decreasing production of both InF and HCL due to cell
damage, and by secreting Abs to InF from plasma cells, the autoimmune atrophie gastritis causes 612
deficiency and pernicious anemia.

30% of autoimmune thyroiditis patients have been found with serum Abs to parietal cells. Conversely,
thyroid Abs have been demonstrated in up to fifty percent of pernicious anemia patients. These Abs are not
cross-reacting types and must be products of two different clones. Such multiplicity of autoimmune
responses has been discussed in connection of defective production of T cells and emergence of "forbidden
clones".

Autoimmune Hemolytic Anemia

Abs reactive to one's own RBCs are found in the patients suffering from this disorder. Although these anti-
RBC Abs do not show hemolytic activity in vitro, they have been found to a accelerate the destruction of RBCs
in vivo: normal red cells coated with auto-Abs have a shortened half life after reinjection into the normal
subject. Similarly normal red cells also have a shortened survival when transfused into patients with
hemolytic anemia, but only when they possess the Ags against which the patient's auto-Abs are directed,
implying that the destructive process must be linked to an auto immune response. The opsonized (Ab-
coated) RBCs are phagocytosed by macrophages and broken down mostly in the spleen. Non-specific
immunosuppression and splenectomy (removal of spleen) are the methods of treatment for the disease.

Coombs test is used for the detection of this disorder. Auto-Abs coated on the patient's red cells are
demonstrated by agglutination of the RBCs in the presence of rabbit antiserum to human Igs.

In the indirect test, RBCs from a normal person are first coated with the patient's serum containing auto-Abs
and then subjected to clumping by the rabbit anti-serum.

In most cases, the NZB strain of mice develops hemolytic anemia as they age. Viable Ab-forming lymphoid
cells from affected older animals can efficiently transfer the disease to young, unaffected mice of the same
strain. The possible mechanism for the onset of the disease has been discussed earlier.

Thrombocytopenic Purpura

Auto-Abs to platelets are considered responsible for thrombocyíopenic purpura. In this disease, platelet
count declines sometimes to about one-tenth of the normal level and consequently bleeding occurs in many
organs and skin causing rashes and purpura. The autoimmune nature of this disease was first understood
when a human volunteer injected with a patient's plasma suffered a serious decline in the number of platelets
and extensive bleeding into the internal organs and skin. Active principle (IgG} from patients plasma could
also be absorbed out with platelets. The transient neonatal thrombocytopenia which may be found in infants
of mothers afflicted with this disease is due to placental transmission of the maternal auto-Abs (IgG).

Allergic Encephalomyelitis

Laboratory animals, such as rats, guinea pigs, rabbits, monkeys, injected with a suspension of myelin-
containing tissue of the central nervous system from members of the same or other species develop patchy
regions of vasculitis and demyelination in the brain and spinal cord. This response may also be induced with
a single injection of a small amount of central nervous system tissue, even from the same animal, in Freund's
complete adjuvant.

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Author : Dr. Saurav K Sarkar Designation : Lecturer
Discipline : B. Tech (Biotech) Module : BT 501 Semester : VI
Topic : Autoimmunity

This disorder ultimately may lead to paralysis. Sections of the brain of the diseased animals show focal
inflammations in myelinated tissue with perivascular infiltration by mononuclear cells which include
lymphocytes. The lymphocytes from sensitized individuals have been found to cause specific neural lesions in
non-sensitized syngeneic recipients. Intradermal inoculation of myelinated tissue evokes a delayed type skin
reaction in the affected animals. Although serum Abs to brain tissue can be detected, they seem to play no
major role in the disorder; serum usually fails to transfer lesions to the recipient animals.

A small protein of 18,000 da constituting 30% of the protein in myelin acts as the antigen for the induction of
this disorder, and a nine amino acid residue fragment of this protein is mainly encephalitogenic.

Experimental studies with animals helped in understanding the etiology of encephalitis in humans after
injection of the rabies vaccine prepared from infected rabbit brain. That is why, nowadays, rabies vaccine
from virus grown is human cultured cell lines other than neural cells or in duck embryo tissues lacking
myéline is in much use.

Rheumatoid Arthritis

IgG in immune complexes is capable of evoking the formation of auto-Abs, the so-called rheumatoid or anti-
globulin factors which can be demonstrated in the sera of virtually all patients with rheumatoid arthritis. The
majority have IgM anti-globulins which react in the classical agglutination tests. The anti-globulin Abs react
with the Fc portion of IgG adsorbed onto latex particles; agglutination of the latex particles can be seen
easily.

Aggregated IgG in the form of complexes are present in the synovium and the synovial fluid and
polymorphonuclear neutrophils can be detected in the affected joints of patients with rheumatoid arthritis.
When sera of rheumatoid patients are kept at 4°C, commonly cry o précipitât e s of aggregated IgG and anti-
globulin develop. Complement levels in the synovial fluid of the patients are low due to its participation in
the immune complexes. These complexes are phagocytosed by the infiltrating polymorphs and their
phagocytosis leads to the release of lysosomal enzymes which ultimately cause the inflammatory reactions
and pain within the affected joint.

Rheumatoid arthritis is a common autoimmune disorder, most often affecting women from 40 to 60 years
old. Besides chronic inflammation of the joints as major symptom, the hématologie, cardiovascular and
respiratory systems are also frequently affected.

Microscopical examinations indicate heavy infiltration of the synovium by lymphoid cells including plasma
cells which often aggregate in the form of lymphoid follicles; the synthesis of IgG at these sites can be as high
as that of a stimulated lymph node. Now the question is whether IgG itself is the initiating antigen for this
response or is the synthesis of anti-globulin to immune complexes secondary to the formation of complexes
involving an endogenous Ag at the joint or an exogenous agent like a microorganism. There are evidences
that a number of mycoplasme strains may cause arthritis in different animals.

Insulin-dependent (Type 1) Diabetes Mellitus

Chronic autoimmune reactions are now thought most likely to play a key role in the progressive destruction
of the insulin-producing β cells in the islets of Langerhans.

The discovery of circulating islet-cell antibodies (ICA) first in Type l diabetic patients with other associated
autoimmune endocrine problems and subsequently in diabetic patients without any other autoimmune
diseases initiated the conceptual changes on the earlier stand. About 50-80% of type 1 diabetic patients have
ICA and the family members of such patients often show the presence of ICA preceding the clinical
manifestation of diabetes occurring after several years. Furthermore, in recent years, spontaneous insulin
autoantibodies (IAA) have been detected in diabetic patients before insulin treatment and interestingly their

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Author : Dr. Saurav K Sarkar Designation : Lecturer
Discipline : B. Tech (Biotech) Module : BT 501 Semester : VI
Topic : Autoimmunity

presence has been noted even in the prediabetic phase. Thus, it is now generally agreed that Type 1 diabetes
might often have a clinically symptomless prediabetic period, characterized by circulating ICA and IAA.

Destruction of β cells by autoantibodies may be carried out either by Ab plus complement mediated lysis or
antibody-dependent ceil-mediated cytotoxicity (ADCC), or both. A large number of TDTH cells also infiltrate
the islet of Langerhans and the condition is described as insulitis. A cell mediated DTH response develops
following the infiltration and activation of large number of macrophages and subsequent release of lytic
enzymes from macrophages cause destruction of the β cells, Cytokines like IFN-γ, TNF and IL-1 have also
been implicated in the destruction of the β cell.

The elucidation of the pathogenesis of β cell destruction and onset of the disease process from autoimmunity
point of view will help in the development oí some means of abrogating or preventing chronic destruction of
the β cells in the near future.

Systemic Lupus Erythematosus

This is a very complex disease wherein a variety of auto-Abs are formed to various blood cells, clotting
factors, and intraceîluîar components, such as mitochondria, DNA and other nuclear constituents.
Pathological changes are widespread and primarily occur as lesions of the connective tissue with fibrinoid
necrosis. They are seen in the skin, like the characteristic 'lupus1 butterfly rash on the face, in kidney
glomeruli, joints, serous membranes and blood vessels. In addition, this disorder includes hemolytic anemia,
lymphopenia, thrombocytopenic purpura and bleeding tendencies. This autoimmune disease typically
appears in women between 20 and 40 years of age with a female : male ratio of 10:1.

Auto-Abs to DNA cause deposition of Ag-Ab-C complexes in the walls of small blood vessels, leading to
widespread Arthus lesions; deposition of the complexes in the capillaries of renal glomeruli can lead to
glomerulonephritis and renal failure and ultimate fatality. On incubation of blood or bone marrow from
patients, the breakdown of some cells apparently releases DNA which combines with serum anti-DNA Abs;
the resulting Ag-Ab complexes are taken up by granulocytes. Then the granulocytes acquire a characteristic
appearance with a central large amorphous mass and their multilobed nucleus pushed to the periphery; these
cells are known as lupus erythematous (LE) cells and their appearance is diagnostic for the disease.

The production of many auto-Abs is indicated by high serum Ig levels during the active phase of the disease;
simultaneously serum C levels fall as it binds to the immune complexes. The antibodies to DNA have been
found polyreactive, especially with phospholipids which suggest the possible existence of an alternative
immunogen to DNA. Data show that T cell tolerance developed in thymus is of potential importance in
establishing tolerance to nuclear antigens.

Therapy for Autoimmune Disorders

Ideal goal for treatment of autoimmune diseases should be the removal of the causative factors for the
autoimmune responses while leaving the rest of the immune system and response intact. Means to achieve
such a goal are not yet in sight. Thus, recent therapies for autoimmune diseases are more of palliative than
permanent cure. The major strategy of the treatments is to suppress the immune system; the suppression
does not distinguish between a pathologic autoimmune response and a much needed protective immune
response.

One of the best therapeutic approaches for the systemic lupus erythematosus appears to be the use of
corticosteroids which help to suppress the inflammatory lesions and prolong the life of the patients and they
remain in the mainstay of intensive therapy. As for the possible modes of action against the disease, both the
anti-inflammatory and immnunosuppressive properties of the steroids have been cited.

More potent immunosuppressive (and cytotoxic) agents such as cyclophosphamide and azathioprine have

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Author : Dr. Saurav K Sarkar Designation : Lecturer
Discipline : B. Tech (Biotech) Module : BT 501 Semester : VI
Topic : Autoimmunity

been reported to retard the progression of autoimmune renal disease in mice. Recent studies have shown
favorable results in human patients treated with intermittent intravenous cyclophosphamide or the
combination oí oral cyclophosphamide and oral azathioprine. However, general immunosuppression puts
the patient at greater risk for infection or the development of cancer. In recent time, somewhat selective
approach employs cyclosporin A for treatment of autoimmunity. This drug inhibits intracellular signal
transduction by the T cell receptor only in antigen activated T cells, sparing nonactivated ones.

Plasmapheresis is a process to remove plasma from a patient's blood by continuous flow centrifugation. The
RBCs are resuspended in suitable medium and returned to the patient's circulation. In this process, Ag-Ab
complexes in autoimmune plasma are removed along with the plasma. This provides short term relief to the
patients with Grave's disease, myasthenia gravis, rheumatoid arthritis, or systemic lupus erythematosus.
Removal of abnormal thymus, with thymic hyperplasia or thymomas, is suggested in some cases of
myasthenia gravis. In cases of organ specific disease, supplement therapy is normally followed; for example,
vitamin Bi2 in pernicious anemia, thyroxin in primary myxoedema. Anti-inflammatory drugs like aspirin are
often used in rheumatoid arthritis. If and when microorganisms would be convincingly implicated as the
causative agent for this disease, they would obviously be the target for chemotherapeutic treatment.