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Autoimmunity
Autoimmune diseases result from the destruction of self proteins, cells, and organs by
auto-antibodies or self-reactive T cells
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Autoimmune diseases can also be categorized based upon the
immune component that does the bulk of the damage: T cells or antibodies
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Hashimoto’s thyroiditis is prevalent in middle aged women
...
The resulting delayed-type
hypersensitivity response is characterized by an intense infiltration of the thyroid gland by
lymphocytes, macrophages, and plasma cells, which form lymphocyte follicles and germinal
centres
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The ensuing inflammatory response causes a goiter, or
visible enlargement of the thyroid gland, a physiological response to local inflammation
caused by antibodies against thyroid specific proteins
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Hashitmoto’s thyroiditis is treated with replacement therapy
involving daily administration of thyroxine
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The disease begins with
cytotoxic T lymphocyte infiltration and activation of macrophages, referred to as insulitis,
which leads to a cell-mediated delayed type hypersensitivity response, with resulting
cytokine release and production of autoantibodies
...
Antibodies specific or beta cells
contribute to cell destruction by facilitating either antibody-mediated complement lysis or
antibody-dependent cell-mediated cytotoxicity
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The late stages of
the disease can be charcterized by atheroscleortic vascular lesions (which cause gangrene
of extremities due to impeded vascular flow), renal failure, and blindness
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T1D is treated by daily administration of insulin
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One of the best studied animal models of
this disease is the nonobsese diabetic (NOD) mouse, which spontaneously develops a form
of diabetes that resembles human T1D
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NOD mice housed in

germ-free environments show a higher incidence of diabetes compared with those in regular
housing, suggesting that a diverse flora may help block development of autoimmune
disease
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In addition, the anti-AChR auto-antibody activates
complement mediated lysis of the cells which damages the motor end plate of the muscle
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Ultimately, the antibodies
cause the destruction of cells bearing ACh receptors
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Without treatment,
progressive weakening of the muscles can lead to severe impairment in eating as well as
problems with movement
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using
cholinesterase inhibitors), decreasing antibody production (using corticosteroids or other
immunosuppressants), and/or removing antibodies (via plasmapheresis: the removal and
exchange of blood plasma)
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The rabbits develop antibodies against the AChR that cross reacted
with their own AChRs
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Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) has a higher incidence in women than men, and a
higher incidence in African American and Hispanic women than white women, SLE
symptoms appear between 20-40 years of age
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SLE presents clinically with fever, weakness, arthritis, kidney dysfunction, and a
characteristic butterfly rash across the nose and cheeks
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When immune complexes of auto-antibodies
with various nuclear antigens are deposited along walls of small blood vessels, a type III
hypersensitivity reaction develops
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In
severe cases, excessive complement activation produces elevated serum levels of certain
complement fragments, leading to neutrophil aggregation and attachment to the vascular
endothelium
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Laboratory diagnosis of SLE involves detection of antinuclear antibodies
directed against DNA, nucleoprotein, histones, or nucleolar RNA
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The New Zealand mouse is an animal model for SLE
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NZB/W F1 mice develop

autoimmune haemolytic anaemia between 2-4 months of age, at which point auto-antibodies
can be detected
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Individuals with MS produce autoreactive CD4+ T cells
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Since myelin functions to insulate the nerve fibres, a
breakdown in the myelin sheath leads to numerous progressive neurologic dysfunctions,
ranging from numbness in the limbs to paralysis or loss of vision
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MS has both genetic and environmental associations
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The environmental
factors that may impact MS susceptibility include; diet, smoking, obesity or BMI, and vitamin
D levels
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Studies in patients with MS have noted
disruption in the gut flora associated with flare-ups
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MS is induced in small animals by
immunization with myelin basic protein or proteolipid protein, both components of the myelin
sheaths surrounding neurons in the CNS
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Germ-free mice are less
susceptible to induction of MS, and addition of particular gut commensals has been shown to
either exacerbate or attenuate disease, highlighting the role of diet and the microflora in
disease susceptibility
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RA has a strong genetic susceptibility
component, the HLA-DRB1 locus is implicated
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Individuals with RA produce antibodies that react with citrullinated protein antigens
(where an arginine residue is converted to the nonstandard amino acid citrulline)
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The
classic RF is an IgM antibody
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These can activate the complement cascade, resulting
in a type III hypersensitivity reaction and chronic inflammation
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RA is associated with gum disease and bacteria that cause gingivitis, as well as with
smoking
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Triggering or exacerbating the production of anti self antibodies in individuals who
are already susceptible to RA
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Enteropathy, X-linked syndrome
Autoimmune polyendocrine syndrome type-1 (APS1), and immune dysregulation,
polyendocrinopathy
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APS-1 and IPEX; are monogenic disorders, impact multiple organs, and display

a range of immune pathologies (endocrine dysfunction, autoimmunity and primary immune
deficiency)
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The AIRE transcription factor ensures tha tissue specific antigens are expressed in
the thymus during T cell development
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IPEX is caused by mutations in the FoxP3 gene, the master transcriptional regulator
associated with regulatory T cells, which are generated both during central and peripheral
tolerance
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However, two individuals can have exactly the same
set of MHC alleles (monozygotic twins) and still be discordant for the development of
autoimmune disease
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The strongest
association between HLA allele and autoimmunity is seen in ankylosing spondylitis (AS)
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Other non-MHC immune genes are also associated with autoimmune
disease
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Genes may have cumulative effects on susceptibility to autoimmune diseases
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genes for; cytokines and their
receptors, antigen processing and presentation, C-type lectin receptors, signaling pathways,
adhesion molecules, and co stimulatory or inhibitory receptors, have all been linked to
specific autoimmune disease
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This suggests a link between environmental and/or lifestyle factors, and the
development of autoimmune diseases
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Certain gut
microbes or their secreted products make contact with immune cells in the intestinal mucosa
and elsewhere on body surfaces, and regulate peripheral tolerance and suppress induction
of autoimmunity
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Th17 cells may be an important driver of multiple autoimmune diseases
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The microbiome
has a role in systemic immunity
...

Exposure to carcinogens or infectious agents that favor DNA damage or polyclonal
activation can interfere with regulation of self-reactive T and B cells and/or lead to the
expansion and survival of rare T or B cell clones with autoimmune portnetial
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The molecular mimicry hypothesis posits that some pathogens express protein
epitopes resembling self compounds, either in conformation or primary sequence, and when
these enter the body they inadvertently activate self-reactive cells in a proinflammatory
microenvironment, bypassing immune regulation
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Broad-spectrum therapies for autoimmune disease
Broad-spectrum immunosuppressants do not cure autoimmune diseases but do reduce
symptoms and improve patients quality of life
...
They suppress
lymphocytes indiscriminately, by inhibiting their survival and proliferation, or by killing rapidly
dividing leukocytes, thus inhibiting overall inflammation throughout the body
...
hair follicles, intestinal lining,
blood cells), an increased risk of uncontrolled infection, and even the development of cancer
...
Plasmapheresis may also provide significant if short-term
benefit for diseases involving antigen-antibody complexes (eg
...

Strategies that target specific cell types
When antibodies and/or immune complexes are heavily involved in autoimmune pathology,
strategies aimed at killing or blocking B cell specific antigen CD20 (rituximab) depletes a
subset of B cells and provides short term benefit for patients with RA
...
anti-CD4 monoclonal antibodies, such as zanolimumab, partially
deplete CD4+ T cells, and are used in the treatment of arthritis
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Current research into strategies that target
specific cell types is directed toward mimicking Treg-like mechanisms of suppression, eg
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by using IL-17 or IL-23 blocking antibodies
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These would be more
targeted than broad-spectrum anti-inflammatories and might therefore spare some arms of
the immune response to still work to protect us from foreign invaders
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IL-1 receptor antagonists, antibodies
directed against the IL-6 receptor and IL-15 are used in the treatment of RA
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All these treatments have some
side effects that overlap with broad spectrum antiinflammatory drugs, plus they are all much
more expensive
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CRP is an indicator
of inflammation
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Stains may be used in the treatment of RA and
MS
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Compounds that block
the chemokine or adhesion molecule signals controlling lymphocyte movement into sites of
inflammation can also inhibit autoimmune processes
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This compound is an analog of sphingosine and induces internalisation of
sphingosine 1-phosphate (S1P) receptors in the body, which are involved in the migration of
lymphocytes into blood and lymph nodes
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Fingolimod also inhibits Th1 and
Th17 cells, and enhances Treg cell activity
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Natalizumab is a monoclonal antibody specific for the adhesion molecule alpha 4 integrin
and is used in the treatment of MS
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However, a significant number of patients developed a life-threatening CNS infection
in response to Natalizumab
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Therapies that interfere with costimulation
T cells require both antigenic stimulation via the T cell receptor (signal 1) and costimulation
(signal 2) to become fully activated
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CTLA-4 is a potent inhibitor of T cell
activity, binding to CD80/86 with a high affinity
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This therapeutic fusion protein drug, Abatacept, was approved
for the treatment of RA and is designed to block CD8-/86 on antigen presenting cells from
engaging with CD28 on T cells, inhibiting costimulation
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Qatiramer acetate, a polymer of four basic amino acids
found commonly in myelin basic protein, has been approved for treating MS
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Quintana, et al
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In vitro, treatment of murine dendritic cells with these
nanoparticles induced a tolerogenic phenotype, suppressed proinflammatory cytokine
production, and led to differentiation of T cells into a regulatory phenotype
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