Tolerance & Autoimmune Disease

Dr.Anam Zamin
M.Phil. (P harmaceutics)
Lecturer
 TOLERANC
E is specific immunologic unresponsiveness (i.e., an
⚫ Tolerance
immune response to a certain antigen [or epitope] does not occur,
although the immune system is otherwise functioning normally).
⚫ 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).
⚫ On the other hand, antigens that are not present during the process
of maturation (i.e., that are encountered first when the body is
immunologically mature) are considered “nonself ” and usually elicit
an immunologic response.
⚫ Although both B cells and T cells participate in tolerance, it is T-
cell tolerance that plays the primary role.
 T-Cell
⚫ TheTolerance
main process by which T lymphocytes acquire the ability
to distinguish self from nonself occurs in the fetal thymus.
⚫ This process, called clonal deletion, involves the killing of T
cells (“negative selection”) that react against antigens
(primarily self
major histocompatibility complex [MHC] proteins) present in the
fetus at that time.
⚫ The self-reactive cells die by a process of programmed cell death
called apoptosis.
⚫ Tolerance to self acquired within the thymus is called central
tolerance, whereas tolerance acquired outside the thymus is
called peripheral tolerance.
⚫ Peripheral tolerance is necessary because some antigens are not
expressed in the thymus and therefore some self-reactive T cells
are not killed in the thymus.
⚫ There are several mechanisms involved in peripheral tolerance:
Some self-reactive T cells are killed, some are not activated, and
others are suppressed by regulatory T cells producing inhibitory
cytokines.
 B-Cell
Tolerance
⚫ B cells also become tolerant to self by two mechanisms: (1) clonal
deletion, probably while the B-cell precursors are in the bone
marrow, and (2) B cells in the periphery.
⚫ However, tolerance in B cells is less complete than in T cells.
 AUTOIMMUNE
DISEASES
⚫ The adult host usually exhibits tolerance to tissue antigens
present during fetal life that are recognized as “self.”
⚫ However, in certain circumstances, tolerance may be lost and
immune reactions to host antigens may develop, resulting in
autoimmune diseases.
⚫ 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.
⚫ Most autoimmune diseases are antibody-mediated.
 Genetic
Factors
⚫ Many autoimmune diseases exhibit a marked familial incidence,
which suggests a 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.
⚫ It should be noted, however, that whether a person develops an
autoimmune disease or not is clearly multifactorial, because people
with HLA genes known to predispose to certain autoimmune
diseases nevertheless do not develop the disease
⚫ That is to say, HLA genes appear to be necessary but not sufficient
to cause autoimmune diseases.
 Hormonal
Factors90% of all autoimmune diseases occur in
⚫ Approximately
women.
⚫ Although the explanation for this markedly unequal gender ratio is
unclear, there is some evidence from animal models that estrogen
can alter the B-cell repertoire and can alter the formation of
antibody.
⚫ 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.
 Environmental
Factors
⚫ 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.
⚫ 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.
⚫ Other environmental triggers include certain drugs such as
procainamide, which causes systemic lupus erythematosus, and
certain heavy metals such as gold and mercury, which cause
autoimmune diseases in experimental animals.
Microbial Infections Associated
with Autoimmune Diseases
 Mechanism
s
⚫ The following main mechanisms for autoimmunity have been proposed.
⚫ 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.
⚫ There are also identical amino acid sequences in certain viral
⚫ Alteration of Normal Proteins
⚫ Drugs can bind to normal proteins and make them immunogenic.
⚫ Procainamide induced systemic lupus erythematosus is an example
of this mechanism.
⚫ Release of Sequestered Antigens
⚫ Certain tissues (e.g.,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 encephalitis, or endophthalmitis, respectively.
⚫ Intracellular antigens, such as histones, and mitochondrial
enzymes, are normally sequestered from the immune
system.
⚫ However, bacterial or viral infection may damage cells and
cause the release of these sequestered antigens, which then elicit
an immune response.
⚫ Once autoantibodies are formed, subsequent release of
sequestered antigens results in the formation of immune
complexes and the symptoms of the autoimmune disease.
⚫ In addition to infection, radiation (UV) and chemicals can
also damage cells and release sequestered intracellular
components.
 Diseases Involving Primarily One
Type of Cell or Organ
⚫Psoriasis
⚫ Psoriasis is a chronic autoimmune skin disease characterized by
raised erythematous plaques with silvery scales, often on the
elbows or knees.
⚫ Skin lesions are the most common manifestation, but
psoriatic arthritis also occurs.
⚫ Methotrexate, cyclosporine, monoclonal antibodies and
TNF inhibitors and infliximab are also used.
 Diseases Involving Multiple
Organs (Systemic
⚫Systemic Diseases)
lupus erythematosus
⚫ Autoantibodies are formed against DNA, histones, nucleolar proteins,
and other components of the cell nucleus.
⚫ However, two drugs, procainamide and hydralazine, are known to
cause systemic lupus erythematosus.
⚫ Most of the clinical findings are caused by immune complexes that
activate complement and, as a consequence, damage tissue.
⚫ Characteristic rash on the cheeks, arthritis, anemia, leukopenia,
thrombocytopenia and glomerulonephritis commonly seen in
systemic lupus erythematosus
⚫ Treatment of systemic lupus erythematosus varies depending on the
severity of the disease and the organs affected.
⚫ Aspirin, nonsteroidal antiinflammatory drugs, and corticosteroids
are commonly used.
 Treatment
⚫ 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 azathioprine
and methotrexate, can be added.
⚫ Immunosuppressive therapy must be given cautiously because
of the risk of opportunistic infections.