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BASIC CONCEPT OF AUTOIMMUNITY

Definition: Autoimmunity is a condition in which structural and functional damage is produced by the
action of antibodies or immunologically competent cells against the normal components of the body.
Ideally at least 3 requirements should be met before a disorder can be categorized as TRULY DUE TO
AUTOIMMUNITY -------------
(1) The presence of an autoimmune reaction
(2) Clinical or experimental evidence that such a reaction is not secondary to tissue damage but is of
primary pathogenetic significance
(3) There is absence of another well defined cause of the disease.

Since autoimmunity implies a loss of self tolerance, it is important to understand the mechanism of
immunological tolerance.

IMMUNOLOGICAL TOLERANCE:
Immunological tolerance is a state in which the individual is incapable of developing an immune
response to a specific antigen. SELF TOLERENCE REFERS TO LACK OF RESPONSIVENESS TO AN
INDIVIDUAL’S ANTIGENS. Several mechanisms have been postulated to explain the tolerant state, 3 are
worthy of consideration -----
 CLONAL DELETION
 CLONAL ANERGY
 PERIPHERAL SUPPRESION.

(A) CLONAL DELETION: This refers to loss of self reactive T and B lymphocytes during their maturation
in the thymus and bone marrow respectively. T cells that bear receptors for self antigens are
deleted within the thymus when these self antigens are presented to them in relation to self MHC
molecules --------- therefore the peripheral T cell pool is lacking or deficient in self reactive T cells.
This is the same also for B cells when they encounter membrane bound antigen within the bone
marrow.
(B) CLONAL ANERGY: This refers to prolonged or irreversible functional inactivation of lymphocytes
when they encounter antigens under certain conditions. For example, it is well established that
activation of antigen specific CD4+ T cells requires 2 signals ------- recognition of peptide antigen in
association with class II MHC molecules on the surface of APCs and a set of second co-stimulatory
signals provided by the APCs. This includes binding of T cell associated molecules (CD28) to its
ligand on the APC (called B7). If the antigen is presented by cells that do not have B7 then the T
lymphocyte gets anergic.
A special form of peripheral unresponsiveness may occur if a T cell that bears receptors
for self antigens encounters the antigen on a cell that does not express MHC class II molecules.
Clonal anergy affects B cells as well . it is believed that if B cells encounter antigen before
they are fully mature, the antigen receptor complex is endocytosed and such cells can never reexpress
their immunoglobulin receptors. They are unable to respond to subsequent antigenic stimulation.
(C) PERIPHERAL SUPPRESION BY T CELLS -------- although the above two mechanisms are mainly
responsible for immunological tolerance, there are additional mechanisms also. Many factors, both
cellular and humoral that can actively suppress autoreactive lymphocytes have been described.
Most interest however has focused on suppressor T cells. These cells are CD8+ T lymphocytes and
probably secrete cytokines like TGF-beta that downregulate the immune responses.

MECHANISMS OF AUTOIMMUNE DISEASES:


4 general mechanisms for loss of self tolerance have been postulated -----------
(A) BYPASS OF HELPER T CELL TOLERENCE
(B) MOLECULAR MIMICRY
(C) IMBALANCE OF SUPRESSOR-HELPER T CELL FUNCTION
(D) EMERGENCE OF A SEQUESTERED ANTIGEN
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BYPASS OF HELPER T CELL TOLERENCE :


Tolerance of Helper T cells is critical to the prevention of autoimmunity. Break in the tolerance can
occur in following circumstances ---------------
(a) Modification of the self antigens by complexing with drugs or organisms which will be recognized as
foreign by the lymphocytes. Eg. Autoimmune hemolytic anemia associated with drugs like alpha
methyldopa.
(b) Partial degradation of autoantigen will expose new antigenic determinants that will be recognized
as foreign by the lymphocytes. Partially degraded collagen and enzymatically altered thyroglobulin
or gamma globulin are more immunogenic than their native species.
Eg. The autoantibodies to gamma globulin (rheumatoid factor) induced during some bacterial, viral and
parasitic infections may well be due to alterations of gamma globulin by either the microorganisms or
lysosomal hydrolases.
(c) Several infectious agents cross react with human tissues through their haptenic determinants (B
cell epitopes). The infecting microorganisms may trigger an antibody response by presenting the
cross reacting heptenic determinant in association with their own carrier. The antibody so formed
may then damage the tissues having the cross reacting determinants. This is called as MOLECULAR
MIMICRY. ONCE THE INFECTIOUS AGENTS PROVOKE TISSUE DAMAGE, THEIR CONTINUED PRESENCE
IS NOT NECESSARY AS TISSUE INJURY RELEASES MORE SELF ANTIGENS. Molecular mimicry or cross
reactions may also apply to T cell epitopes.
Eg. There is some evidence that rheumatic heart disease sometimes follows streptococcal infection
because an antibody to streptococcal M protein cross reacts with M protein in the sarcolemma of
cardiac muscle.

POLYCLONAL LYMPHOCYTE ACTIVATION:


Several microorganisms and their products are capable of causing polyclonal activation of B
cells. The best investigated among these is bacterial lipopolysaccharide (entotoxin). Infection of B cells
with EBV could also achieve the same effect because B cells bear receptors for EBV.

IMBALANCE OF SUPPRESSOR-HELPER T CELL FUNCTION:


Any loss of suppressor T cells functions will contribute to autoimmunity and conversely
excessive T cell help may drive B cells to extremely high levels of autoantibody production. There are
some experimental evidence in support of this --------- there is an age associated loss of suppressor T
cells in mice that develop an autoimmune disease similar to SLE as they age. Defects in suppressor
cell function and numbers (or both) have been reported in human SLE.

EMERGENCE OF A SEQUESTERED ANTIGEN:


It is clear that induction of tolerance requires the interaction between the antigen and the
immune system. Thus any self antigen that is completely sequestered during embryonic development
was not presented to the lymphocytes during their maturation and the subsequent lymphocytes
reactive against them were not clonally deleted. Therefore if these sequestered antigens are later
released into circulation they will not be recognized as self and an immune response will develop
against these self antigens.

GENETIC FACTORS IN AUTOIMMUNITY:


Evidences are -------------
(a) Familial clustering of many autoimmune diseases
(b) Linkage of several autoimmune diseases with HLA especially class II antigens.
(c) Induction of autoimmune diseases in transgenic mice.

The precise mechanism by which genes predispose to autoimmunity is not clear but attention
is focused on the relationship of autoimmunity to class II MHC molecules. At least 2 mechanisms can
explain this association ----------------
 CD4+ helper cells are triggered by peptide antigens bound to class II MHC molecules. A class II
allele that can bind to a given self antigen may facilitate an autoimmune response.
 During the process of clonal deletion during embryonic life, if a particular MHC class II molecule
presented the antigens poorly to the T cells then the relevant autoreactive T cell clone will not be
deleted. Individuals who inherit such class II molecules may therefore be at an increased risk for
developing autoimmunity.
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TESTS FOR THE DETECTION OF AUTOANTIBODIES ----------
1. Immunoprecipitation test
2. Flocculation and agglutination test
3. CFT
4. Passive cutaneous anaphylaxis test
5. Immunoflourescent tests
6. ELISA

IMMUNOPRECIPITATION TESTS:
When a soluble antigen combines with its antibody in the presence of electrolytes (NaCl) at a suitable
temperature and pH, the antigen antibody complex forms an insoluble precipitate. When instead of
sedimenting, the precipitate remains suspended as floccules, the reaction is known as flocculation.
Precipation an take place in liquid media or in gels such as agar, agarose or polyacrylamide.
The amount of precipitate that will form will greatly be influenced by the relative proportions of
antigens and antibodies. If to the same amount of antiserum in different tubes, increasing amounts of
antigens are added, precipitation will be found to occur more rapidly and adequately in one of the middle
tubes in which the antigen and antibody are present in optimal or equivalent proportion. In other tubes,
precipitation is either weak or absent. FOR A GIVEN ANTIGEN ANTIBODY SYSTEM, THE EQUIVALENT RATIO
IS CONSTANT irrespective of the quantity of the reactants. If the amount of precipitate is plotted in a
graph, there are 3 phases --------- an ascending part (PROZONE or zone of ANTIBODY EXCESS), a peak
(zone of EQUIVALENCE) and a descending part (POSTZONE or zone of antigen excess). The prozone is of
importance in clinical serology as sometimes sera rich in antibody may give a false negative precipitation
or agglutination result unless serial dilutions are tested.

FLOCCULATION AND AGGLUTINATION TESTS:


When the antigen is available in a particulate form or if the antigen can be tagged onto particulate
materials Viz. erythrocytes, bentonite or latex particles, then on reacting with the antibodies there is
clumping of particles within minutes ------- checked under the microscope.
Eg. HAEMAGGLUTINATION TESTS ---------- Test using agglutination of erythrocytes
BENTONITE FLOCCULATION TEST ------- using bentonite particles
LATEX AGGLUTINATION TESTS ----- Using latex particles.

PASSIVE CUTANEOUS ANAPHYLAXIS TEST -------- Used to demonstrate IgG antibodies reactive against some
antigens. Patient’s serum is injected intradermally into the shaved skin of guinea pig. after 4-6 hours
guinea pig is given IV or intracardiac injection containing antigen mixed with 5% aqueous evans blue dye
----------- dye gets attached to serum albumin and remains within the circulation.
Antigen given IV permeates out to the skin and reacts with antibody mixed to the mast cells-------
degranulation ----- liberation of histamine ----- increases permeability of blood vessels locally ------ leakage
of serum proteins and evans blue dye ----- blue patch at local site.

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