ASSINGMENT ONE: Discuss autoimmunity using at least two autoimmune

diseases in your discussion(2 to 4 pages single spaced)

Introduction
The term autoimmunity was coined by the great German bacteriologist and immunologist Paul
Ehrlich(1854 -1915) at the beginning of 20th century. He described it as “horror autotoxicus”
meaning, the horror of self-toxicity.https://www.medicinenet.com>main>art[accessed at 19:55hrs,
14th April,2019]

Collectively autoimmune disorders affect approximately 5% of the population of the western

countries and their incidence is on the rise. Autoimmunity is the responses to self-antigens or
antigens associated with micro biota that lead to tissue damage and disease. The gene
rearrangement that occur during lymphocyte development in the central lymphoid organs
inevitably result in the generation of some lymphocytes with affinity for self-antigens. This
assignment will focus on the mechanisms that keep the lymphocyte repertoire self-tolerant and
see how these may fail. The second part will autoimmune disease that illustrate the various
pathogenic mechanisms by which autoimmunity can damage the body.

THE MAKING AND BREAKING OF TOLERANCE

The immune system has evolved multiple mechanisms to prevent self-injury. The most
fundamental principal is underlying these mechanisms is the discrimination of self from non self
but this discrimination is not easy to achieve partly because short peptides derived from the
processing of pathogens antigens can be identical to self-peptides.

The first mechanism proposed for distinguishing between self and non self is that recognition of
antigen by an immature lymphocyte leads to a negative signal causing lymphocyte death or
inactivation. Self was thought to comprise molecules recognized by a lymphocyte shortly after it
began to express its antigen receptors. This is an important mechanism of inducing self-
tolerance in lymphocytes developing in the Thymus and bone marrow. The tolerance induced
at this stage is called Central tolerance. Newly formed lymphocytes are especially sensitive to
to inactivation by strong signals through their antigen receptors whereas the same signals
activate mature lymphocytes in the periphery.

The tolerance induced to antigens recognized after lymphocytes have left the central lymphoid
organs is called peripheral tolerance. An antigenic quality that that correlates with self in the
periphery is recognition in the absence of danger signals that are produced by innate immune
system as a result of tissue damage or infection. Nearly all cells in the body become senescent
and die and many cells routinely undergo turnover at steady state (for example hematopoietic
cells and epithelial cells of the intestines and skin)This occurs by apoptosis(programmed cell
death).In contrast to cell death that results from physical or Microbe associated Molecular
Patterns(DAMPs and PAMPS),death of senescent cells by apoptosis release signals to tissue
phagocytes that generally promote anti-inflammatory response and repress presentation of
antigens in an inactivation form. Thus self-antigens recognized in the context of normal or
physiologic cellular turnover fail to induce proinflammatory cytokines (for example IL-6 or IL-12)
and co-stimulatory molecules (for example B7.1)that would otherwise induce naïve T cells to
undergo effector differentiation.

MECHANISMS THAT NORMALLY PREVENT TOLERANCE

Multiple tolerance mechanisms normally prevent autoimmunity .Mechanisms that normally

prevent autoimmunity may be thought to as succession of check points. Each check point is
partially effective in preventing antigen responses and together ,the check points act
synergistically to provide efficient protection against autoimmunity without inhibiting the
ability of the immune system to mount effective responses to pathogens.

Central deletion or inactivation of newly formed lymphocytes is the first check point of self-
tolerance. Without them, the immune system would be strongly self-reactive and lethal
autoimmunity would occur early in life. The Autoimmune Regulator gene AIRE promotes the
expression of some tissue specific antigens in the Thymic medullary cells, causing the deletion
of immature . Thymbocytes that can react to these antigens. The AIRE(Autoimmune Regulator
Gene) is defective in patients with a rare inherited form of autoimmunity -
APECED(autoimmune polyendocrinopathy – candidiasis ectodermal dystrophy)also known as
autoimmune polyglandular Syndrome Type 1(APS !) that leads to destruction of multiple
endocrine tissues including insulin producing pancreatic islet cells and to fungal infection
particularly candidiasis.

Lymphocytes that bind self antigens with relatively low affinity usually ignore them but in some
circumstances become activated. They are considered ignorant of self but can be recruited into
autoimmune responses if there threshold activation is exceeded by co-activating factors.one
such stimulus is infection. Naive T cells with low affinity for self-antigens can become activated
if the encounter an activated dendritic cell presenting that antigen and expressing high levels of
Co-stimulatory Signals or pro-inflammatory cytokines as a result of the presence of infection.
Another situation in which normally ignorant lymphocytes may be activated is when their auto
antigens are also ligands for Toll like receptors TLRs).The receptors are usually considered to be
specific for Microbe associated molecular patterns but can be found among self molecules.
Antigens in immunologically privileged sites do not induce immune responses, for instance
foreign tissues or grafts placed in the brain and anterior chamber of the eye do not induce
immune response or rejection. Such sites are termed as immunologically privileged sites.
Studies have shown that antigens leave these sites and interact with T cells, however, instead of
eliciting an effector immune response, they induce a tolerogenic response that does not injure
the tissues.

Autoimmune responses can be controlled at various stages by regulatory T cells. Auto reactive
cells that escape tolerance inducing mechanisms can still be regulated so that they do not cause
disease. T reg cells suppress self-reactive lymphocytes .This type of Tolerance is known as
regulatory Tolerance. The key feature of regulatory Tolerance is that regulatory cells can
suppress auto reactive lymphocytes that recognize a variety of different self-antigens as long as
the antigens are from the same tissue or presented by the same antigen presenting cells.
Natural T reg cells (nT reg) cells are programmed in the Thymus to express the transcription
factor FOX P3 in response to self-antigen. When activated by the same antigens in the
peripheral tissues, nTreg cells inhibit other self-reactive T cells that recognize antigens in the
same tissues to prevent their differentiation into effector T cells or prevent their effector
function. Studies have shown that human and Mice that carry Mutations in the genes for FOX
P3 rapidly develop severe systemic autoimmunity. A protective role for FOX P3 expressing Treg
cells has been demonstrated in several autoimmune syndromes in mice including
Diabetes,EAE,SLE and inflammation of large intestines or colon (Colitis)

Auto reactive T cells that express particular Cytokines may be non-pathological or may suppress
pathogenic lymphocytes.CD4 cells can differentiate into various types of effector lineage
namely TH1, TH2, and TH17 .Another subset is T reg. For some autoimmune diseases to occur,
depends on the presence of a particular effector cell. For instance certain T cell a mediated
autoimmune disease such as type 1 Diabetes Mellitus depends on TH1 cells to calls disease
where as others such as Psoriasis (an autoimmune of the skin) depends on TH17 cells.

CLASSIFICATION OF AUTOIMMUNE DISEASE

Autoimmune diseases can be classified into either Organ – specific or Systemic from a clinical
perspective .Disease restricted to specific Organs of the body, known as Organ specific and
those in which many tissues of the body are affected known as Systemic autoimmune disease.
IN both types, disease has a tendency to become chronic. Examples in Organ specific
autoimmune disease include; Hashimoto’s thyroiditis and Grave’s disease which both affect
the Thyroid gland and type 1 Diabetes which is caused by immune attack on insulin producing
pancreatic B cells. Examples of systemic autoimmune are Systemic Lupus Erythematous (SLE),
and Primary Sjogren’s syndrome in which tissues as diverse as the skin, kidneys and brain may
all be affected.
Janeway(2007)

Rheumatoid arthritis (RA) is a chronic disease characterized by inflammation of the

synovium (the thin lining of a joint).As disease progresses, the inflamed synovium invades and
damages the Cartilage, this is followed by bone erosion leading chronic pain, loss loss of
function and disability The discovery that Rheumatoid Arthritis has an association with
particular class II HLA-DR genes of the MHC suggested that are involved in the pathogenesis of
the disease. Data from human and mouse models indicate that early in the disease
development, auto reactive TH 17 cells become activated. Auto reactive T cells provide to B cells
to produce arthritogenic antibodies. The activated TH 17 also produce cytokines that recruit
neutrophils and monocytes /macrophages, which along with endothelial cells and synovial
fibroblasts , are stimulated to produce more pro-inflammatory cytokines such as TNF-alpha,
IL-!, or chemokine (CXC8,CCL2), and finally matrix metalloproteinase, which are responsible for
tissue destruction IL-17A,has been found in high concentration in the synovium and synovial
fluid of rheumatic disease patients which can induce expression of the ligand for receptor
activator of NFkB(RANKL), which stimulates the differentiation of osteoclasts precursors into
mature osteoclasts that resorb bone. Molecular Mimicry theory has been proposed as a
mechanism by which infection initiates and / or exacerbate autoimmune diseases. This theory
proposes that auto reactive T cells have a dual reactivity to both foreign and self-antigens
leaving the vulnerable to foreign insults. Examples of Bacterial infections initiating and
exacerbating autoimmune diseases are Streptococcus Pyogenes, a gram positive hich causes
group A streptococcal infections. Others are gram negative bacteria such as klebsiella
pneumonia and campylobacter jejuni.The infection causes the production of cross of cross
reactive antibodies in response to the bacteria. Antibodies recognize the M proteins (Virulence
factor) and the N-acetyl –Beta-D-glucosamine of streptococcus pyogenes and reacts self-
proteins. http://www.ncbi.nlm.nih.gov>articles[ accessed at 19:44hrs, 14th April,2019]

Myasthenia gravis: auto antibodies produced against acetyl choline receptors block
receptor function at the neuromuscular junction, resulting in a syndrome of muscle weakness

Lambert – Eaton Myasthenia Syndrome (LEMS ):,is an auto immune disease in which
the immune system attacks the body’s own tissues .The attack occurs at the connection
between nerve and muscle (the neuromuscular junction)and interferes with ability of nerve
cells to send signals muscle cells. Specifically, the immune system attacks the calcium channels
on nerve endings that are required to trigger the release of neurotransmitter (Acetylcholine.
With fewer calcium channels, the nerve endings release less acetylcholine. In people with
LEMS, the lowered levels of acetylcholine are not sufficient to cause normal muscle contraction,
causing muscle weakness. LEMS symptoms begin with leg weakness, often followed by
weakness in the muscles of the eyes, face and throat.
https://www.mda.org>disease>lambert[accessed at 09:41, 14 th September,2019]

References
1 .Kennth Muphy and Casey weaver. (2007) Janeway’s Immunology.9th Ed.New York,Garland
science

2 .Marrack, P. et al.:(2001) Autoimmune diseases: why and where it occurs. Nat Med .

3. Sastry, Apurba S. et Bhat, Sandhya.(2019) Essentials of Medical Microbiology, Second

Edition. Paras Offset Pvt Ltd,

4. .Sercarz, E.E. et al.(1993) Dominance and crypticity of T cell antigenic determinants. Annu
Rev Immunol

5. http://www.ncbi.nlm.nih.gov>articles

6. https://www.mda.org>disease>lambert[accessed at 09:41, 14 th September,2019]

7.https://www.medicinenet.com>main>art[accessed at 19:55hrs, 14th April,2019]