AUTOIMMUNITY

Our immune system sometimes is the cause of disease rather than the cure. Our body is normally able to
distinguish its own self antigens from non-self antigens and does not mount an immunologic attack
against itself. Sometimes inappropriate responses to self-antigens may occur, as well as inappropriate or
greatly heightened responses to foreign antigens, which, in turn, causes tissue damage. Autoimmunity is
a condition in which structural or functional damage is produced by the action of immunologically
competent cells or Ab against self antigen. It depicts protection against self, but actually implies injury
to itself. The diseases are the results from the destruction of self proteins, cells and organs by auto
antibodies or self reactive T cells. The diseases caused by autoimmunity are called as autoimmune
diseases.

A mature animal’s immune system normally does not respond to that animal’s own tissue. This
acceptance of self cells is known as immunological tolerance. The immune system of a fetus undergoes
the process of tolerance to lose the ability to respond to self-molecules as its development proceeds.

Autoimmunity results from the activation of self reactive T and B cells, along with the factors such as
genetic, environmental, viral, hormonal and psycho-neuro-immunological which affect gene expression
in which it interferes with immuneoregulatory actions. Most autoimmune diseases are polygenic and
affected individuals inherit multiple genetic polymorphisms that contribute to the development of
disease susceptibility.

Not all self-reactive T and B lymphocytes undergo apoptosis during selection in primary lymphoid
organs. Normal healthy individuals are known to possess mature, potentially self-reactive lymphocytes.
The activity of these cells, however, is regulated or suppressed so that they do not respond to the self-
antigens they encounter. When this regulation or suppression breaks down, then humoral or cell-
mediated responses can occur against self-antigens, causing serious and sometimes fatal disease.

Additionally, an immune response against a foreign antigen may be a greater one than is actually
required to eliminate the antigen, or the response may be seemingly inappropriate to the antigen. Thus,
instead of eliminating the antigen with only a localized inflammatory response, extensive tissue damage
and occasionally death occurs.

Autoimmune diseases are often categorized as either organ-specific or systemic, depending on whether
they affect a single organ or multiple systems in the body.
AUTOIMMUNE DISEASES TARGET SPECIFIC ORGANS

Hashimoto’s Thyroiditis: Hashimoto’s thyroiditis is an autoimmune disease of the thyroid gland, most
commonly found in middle-aged women which is characterized by the production of auto-antibodies to
major thyroid proteins, thyroid peroxidase and thyroglobulin hormone. These autoantibodies play a
major role in the destruction of the thyroid gland in which autoantibodies binds to these proteins and
interfere with iodine uptake which leads to hyposecretion of the thyroid hormone causing
hypothyroidism. Sensitized TH1 cells specific for thyroid antigens also contribute to the destruction of
the thyroid gland. T cells as well as B cells, macrophages, lymphocytes, and plasma cells, which form
lymphocytic follicles and germinal centers infiltrate the thyroid. Thus, the thyroid often more closely
resembles a lymphoid follicle with proliferating germinal centers than a gland with epithelial cells lining
the follicles. In some patients the gland, as it attempts to regenerate, may become enlarged, causing a
goiter.
Type 1 Diabetes Mellitus: Type I diabetes mellitus, also referred to as insulin-dependent diabetes
mellitus, is a form of diabetes that involves chronic inflammatory destruction of the insulin-producing β
cells in the islets of Langerhans of the pancreas. This results in little or no insulin production. Insulin
facilitates the entry of glucose into cells, where it is metabolized for energy production. In the absence
of insulin, levels of blood glucose rise, resulting in increased hunger, frequent urination, and excessive
thirst. The major contributors to β-cell destruction are cytotoxic CD8+ T cells. However, inflammatory
infiltrates in the islets of Langerhans include CD4+ T cells and macrophages, along with the cytokines
they secrete, such as IL-1, IL-6, and IFN-α. Many patients with TIDM also develop autoantibodies to
insulin and other islet antigens such as glutamic acid decarboxylase (GAD). It is thought that these
autoantibodies arise as a consequence of β-cell destruction and are not the initial cause of the
destruction.
Myasthenia gravis: Myasthenia gravis is an autoimmune disease mediated by blocking antibodies.
This disease produces auto-antibodies that bind the acetylcholine receptors on the motor end plates of
muscles, blocking the normal binding of acetylcholine and inducing complement mediated lysis of the
cells. The result is a progressive weakening of the skeletal muscles. Ultimately, the antibodies cause the
destruction of the cells bearing the receptors. The early signs of this disease include drooping eyelids
and inability to retract the corners of the mouth. Without treatment, progressive weakening of the
muscles can lead to severe impairment of eating as well as problems with movement. However, with
appropriate treatment, this disease can be managed quite well and afflicted individuals can lead a normal
life. Treatments are aimed at increasing acetylcholine levels decreasing antibody production (using
corticosteroids or other immunosuppressants), or removing antibodies (using plasmapheresis).
SOME AUTOIMMUNE DISEASES ARE SYSTEMIC
Multiple Sclerosis: Multiple sclerosis is an inflammatory, T-cell mediated autoimmune disease
characterized by the demyelination or destruction of the myelin sheaths surrounding central nervous
system nerve axons. This results in lesions in the white matter. As myelin insulates the nerve fibers it
causes several neurologic dysfunctions as numbness in the limbs, chronic progressive paralysis or loss
of vision. T cells play a key role in multiple sclerosis. First, disease susceptibility is associated with the
expression of certain HLA class II alleles. Second, CNS lesions in MS resemble the cellular infiltrates
associated with TH1 cells, reminiscent of delayed-type hypersensitivity. In addition, cytokines and T
lymphocytes are found in CNS plaques. The proinflammatory cytokine IL-17 is made in MS lesions,
and thus that CD4+ TH17 cells may play a role in MS. All these cells contribute to tissue injury.

Rheumatoid Arthritis: Rheumatoid arthritis is an autoimmune disease that causes chronic

inflammation of the joints, resulting in pain, swelling, stiffness, and deformity. Other symptoms include
fatigue, low-grade fever, and loss of appetite. It is characterized by chronically inflamed synovium,
densely crowded with lymphocytes, which results in the destruction of cartilage and bone. In rheumatoid
arthritis the inflamed synovial membrane, usually one-cell thick, becomes so cellular that it mimics
lymphoid tissue and forms new blood vessels. The synovium is densely packed with dendritic cells,
macrophages, T and B cells, NK cells, and plasma cells. In some cases, the synovium develops
secondary follicles. Rheumatoid arthritis individuals produce IgM antibody which are reactive with
determinants in the Fc region of IgG which are rheumatoid factors. When RF binds to IgG, the resulting
immune complexes can deposit in the joints, where they complement and establish an inflammatory
process.
Systemic Lupus Erythematosus: Systemic lupus erythematosus is an autoimmune disease that is more
than nine times more common in women than in men. It is mediated mostly by autoantibodies and
immune complexes, which often deposit in the skin, joints, lungs, blood vessels, heart, kidney, and
brain. Symptoms include fever, skin rashes, joint pain, and damage to the central nervous system, heart,
lungs, and kidneys. The destructive kidney lesions may lead to renal failure. Affected individuals may
produce auto antibodies to a vast array of tissue antigens, such as DNA, histones, RBCs, platelets,
leukocytes and clotting factors. Auto-antibodies specific for RBCs and platelets can lead to complement-
mediated lysis, resulting in hemolytic anemia and thrombocytopenia. When immune complexes of auto-
antibodies with various nuclear antigens are deposited along the walls of small blood vessels, a type III
hypersensitivity reaction develops. The complexes activate the complement system and generate
membrane-attack complexes and complement fragments that damage the wall of the blood vessel,
resulting in vasculitis and glomerulonephritis.
 HYPERSENSITIVITY
Hypersensitivity reaction is an undesirable reactions produced by the normal immune system. It
describes an abnormal or pathologic immune reaction that is caused by an immune response to repeated
exposure to an antigen. Hypersensitivity diseases include autoimmune diseases, in which immune
responses are directed against self-antigens and diseases that result from uncontrolled or excessive
responses to foreign antigens. Because these reactions tend to occur against antigens that cannot be
escaped and because of positive feedback systems intrinsic to various aspects of the immune response,
hypersensitivity diseases tend to manifest as chronic problems. Hypersensitivity reactions occur at
different times after coming into contact with antigens, within a few minutes, minutes to hours or after
many hours. They are usually referred to as an over- reaction of the immune system and these reactions
may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-
sensitized state of the host. Hypersensitivity reactions are antigen specific and occur after the immune
system has been primed. The reactions are therefore mainly the result of antigen specific memory
response and is therefore the effects of the adaptive immune system. Hypersensitivity reactions can be
divided into four types as Type one, type two, type three and type four, based on the mechanisms
involved and time taken for the reaction. Hypersensitivity diseases have been grouped into four major
categories based upon their underlying causes.

1. Immediate hypersensitivity
2. Antibody mediated hypersensitivity
3. Immune complex mediated hypersensitivity
4. Cell mediated hypersensitivity

Type I Hypersensitivity: It is also known as immediate hypersensitivity or allergic reaction which is

induced by antigens known as allergens. It is an IgE mediated humoral antibody responses. The reaction
is the result of the IgE mediated by the binding to IgE specific receptors on mast cells and basophils.
Histamine, serotonin, vasoactive amines and lipid mediators such as platelet activating factor,
prostaglandins are released during the anaphylactic reaction. These substances have the potential to
cause normal consequences of an acute inflammatory reaction such as increased vascular permeability,
smooth muscle contraction, granulocyte chemotaxis, etc. type I hypersensitivity can be anaphylaxis or
atopy. Anaphylaxis can be life threatening, severe whole body allergic reaction caused by re-exposure to
a previously encountered antigen. Atopy is hereditary tendency to develop allergic reaction to
substances such as pollen, food, insect venom etc.
Type II Hypersensitivity: Type II hypersensitivity is also known as cytolytic or cytotoxic
hypersensitivity as it destructs host cells by lysis or toxic mediators. It is caused by antibodies binding to
cells or tissue antigens. This is primarily mediated by antibodies of the IgM or IgG classes and cause
cell destruction by Fc dependent mechanisms. IgG or IgM directed mainly to cellular antigens or surface
auto antigens can cause damage through opsonisation, lysis or antibody dependent cellular cytotoxicity.
It is by the activation of complement system which ultimately forms membrane attack complex and
causes formation of pores in the target cell leading to cell lysis. Diseases caused by this type of
hypersensitivity often involve erythrocytes and self cells.

Two different antibody mediated mechanisms are involved in which complement mediated reactions,
antibodies react with a cell membrane component, leading to complement fixation which activates
complement cascade and leads to cell lysis. Blood cells are commonly affected.

Antibody-dependent mediated cytotoxicity mediates cell destruction in which cytotoxic cells bearing Fc
receptors bind to the Fc region of antibodies on target cells and promote destruction of the cells. Lysis of
the target cells requires contact but does not involve phagocytosis or complement fixation.

Type III Hypersensitivity: It is also known as immune-complex mediated hypersensitivity essentially

with IgG antibodies and soluble antigens. This type of hypersensitivity can be induced by microbial
antigens, auto antigens and foreign serum components. Immune complex mediated hypersensitivity
reactions involve circulating antigen-antibody immune complexes. An immune response in the form of
antibody production against a foreign substance is often mounted to remove any detrimental antigen
from the host.
In type III hypersensitivity, overproduction of immunoglobulins, IgG and IgM to a foreign can lead to
the formation and deposition of excessive amounts of insoluble intermediate-sized immune complexes,
which can be difficult to remove from various tissues by phagocytosis. This in turn may trigger classical
complement activation, leading to overproduction of other inflammatory mediators, leading to the
recruitment, activation and degranulation of peripheral blood granulocytes, such as basophils,
neutrophils to specific tissues, such as the kidneys, lungs and joints culminating in damage. Much of the
tissue damage is the result of complement activation leading to neutrophil chemotraction and release of
lytic enzymes by the degranulating neutrophils. Immune complexes in the skin directly trigger Fc
receptors and activate complement resulting in an acute inflammation response mediated through mast
cells. Immune complexes can also cause systemic effects such as fever, weakness, arthritis and edema.
Depending on the frequency of exposure and route of entry, type III hypersensitivity reactions can
develop over hours, weeks or years.
Type IV Hypersensitivity: Type IV hypersensitivity is also known as delayed type hypersensitivity as
results are observed from 48 hours, which are triggered by antigen-specific T-cells. Unlike the other
types, it is not antibody mediated but rather is a type of cell-mediated response. This is mediated by T-
cell dependent effector mechanisms involving TH cells, primarily of TH1 subtype, but in few cases TC
cells. Antibodies do not act in type IV hypersensitivity reactions. On activation the TH1 cells release
cytokines that cause accumulation and activation of macrophages, which in turn causes local damage.

Type IV hypersensitivity reactions develop when antigen activates sensitized DTH cells. Activation of
DTH cells by antigen on appropriate antigen-presenting cells results in the secretion of various
cytokines, including interleukin 2, macrophage-inhibition factor and tumor necrosis factor β. These
cytokines in turn draw macrophages into the area and activate them, promoting increased concentrations
of lytic enzymes for more effective killing. When inappropriately activated, these reactions can cause
severe tissue injury and fibrosis.

There are two different types of reaction capable of causing tissue injury .The first, known as delayed
type hypersensitivity, is mediated by CD+ helper T cells. The second, known as cell mediated
cytotoxicity is mediated by CD8+T cells together with dendritic cells and, macrophages and cytokines.
Type of hypersensitivity also plays a role in several clinical situations where there is persistence of
antigen which the immune system is unable to remove, leading to chronic inflammation. These reactions
are inappropriate or excessive immune reactions that are mediated by specific subsets of CD+ helper T
cells or by CD+ cytotoxic t cells. Type IV hypersensitivity reaction form the basis of many common
diseases ranging in severity from contact dermatitis to diseases such as type 1 diabetes and viral
hepatitis. Skin contact with a number of small molecules can also result in delayed hypersensitivity.