Lecture set 2

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Lecture set 2
2
Endocrine autoimmunity

• By know you should be getting the feeling that
  the endocrine system is everywhere and interacts
  with everything!
• As it says in your text it is estimated 1 person
  in 30 suffers from some type of recognized
  autoimmune disease.
• There is therefore a strong interaction between
  the endocrine system and the immune system.
• These interactions can be temporary sometimes
  permanent.

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Autoimmune diseases form a spectrum ranging from
organ-specific conditions in which one organ only
is affected to systemic diseases in which the
pathology is diffused throughout the body. The
extremes of this spectrum result from quite
distinct underlying mechanisms, but there are
many conditions in which there are components of
both organ-specific and systemic damage. . Some
pathologies work by shutting a system down
others by hyper stimulating it.
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Autoimmunity

• Although the immune system has an elaborate
  system of checks and balances to ensure self
  tolerance, occasionally this system breaks down.
  When the immune system attacks host components
  causing pathological change, this is called
  autoimmunity. Many people experience an
  autoimmune reaction during their lifetime. Mostly
  these are short-lived, self-resolving sequelae of
  infection. However in some 5 of individuals the
  reaction is chronic, debilitating and even
  (rarely) life-threatening. It is these latter
  conditions where serious immunopathology occurs
  which are usually considered autoimmune disease.
  We shall consider the following aspects
• The characteristics of autoimmune diseases
• Which immune mechanisms are involved in bringing
  about the pathogenic change?
• What factors initiate the autoreactivity?

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Autoantibodies - cause or effect?

• Almost all patients presenting with autoimmune
  conditions have some autoantibodies present in
  their serum. However they also have autoreactive
  T cells present (though these are far harder to
  demonstrate experimentally). It is not always
  known whether the autoantibodies play an
  important role in the disease or are a secondary
  result of the tissue damage which has been caused
  by the disease process itself. This is problem is
  particularly difficult in many organ-specific
  conditions.
• A useful example of the contrast between diseases
  whose destructive mechanism is well understood
  and a similar condition in which it is much less
  well understood is Graves' disease and
  Hashimoto's thyroiditis.
• Both diseases affect the thyroid gland
  specifically, in Graves' the thyroid is
  hyperactive whereas Hashimoto's results in
  thyroid hypoactivity.

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Graves Disease

• This is a rare example of an autoimmune disease
  which can be transferred with IgG antibodies.
  Firstly passive transfer of IgG from patients to
  rats often produces similar symptoms transiently
  in the animals. Secondly babies born to mothers
  with Graves' have shown transient symptoms of
  hyperthyroidism which disappear with catabolism
  of the maternal IgG (transferred via the
  placenta) and are relieved by plasma exchange.The
  disease causing antibodies can be shown to
  recognise the thyroid stimulating hormone (TSH)
  receptor and to stimulate thyrocytes in vitro.

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Hashimoto's Thyroiditis

• This disease is characterised by an intense
  mononuclear cellular infiltrate into the thyroid
  and by the presence of autoantibodies primarily
  directed at thyroglobulin and thyroid peroxidase.
  There are a number of theories about the
  mechanism of pathogenic damage to the tissue.
• Autoreactive T cells (TH1) may cause tissue
  damage by release of cytokines, either directly
  (eg TNF) or by recruiting and activating
  macrophages, which subsequently mediate tissue
  destruction.
• Autoreactive antibodies, whose production
  requires the help of autoreactive T cells, may be
  directly responsible for the pathology, by for
  example interfering with iodine uptake and
  binding by thyroglobulin.
• Inflammation may cause tissue damage by
  triggering apoptosis in thyrocytes by inducing
  expression of a 'death' receptor (Fas, a molecule
  which triggers apoptotic death). Unusually the
  ligand for this 'death' receptor appears to be
  constitutively expressed by thyrocytes. It is
  also expressed by activated but not resting T
  cells.

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Endocrine factors

• Most autoimmune disease do not occur with equal
  frequency in males and females. For example
  Graves' and Hashimoto's are 4-5 times, and SLE 10
  times, more common in females while Ankylosing
  Spondylitis is 3-4 more frequent in males.
  These differences are believed to be the result
  of hormonal influences
• A second well documented hormonal effect is the
  marked reduction in disease severity seen in many
  autoimmune conditions during pregnancy.
  Rheumatoid arthritis is perhaps the classic
  example of this effect. In some cases there is
  also a rapid exacerbation (rebound) after giving
  birth.

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Environment

• However, it is clear that environmental factors
  also play a role in autoimmune disease. If you
  examine how frequently identical twins both
  develop a disease (the concordance rate), it is
  only about 20-40 for common autoimmune diseases
  such as diabetes, SLE and rheumatoid arthritis.
  This makes it highly likely that environmental
  factors must also be important. While we might
  expect factors such as diet to play a role, we
  can postulate that infectious organisms are the
  most significant environmental factor.

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Components of the immune system

• Made up of two cellular systems
• humoral or circulating antiBody system - B cells
• cell mediaTed immunity - T cells
• Both work by identifying antigens (foreign
  proteins or polysaccharides) either as part of a
  virus or bacterium or as a partially degraded
  byproduct
• Also recognizes human antigens not made by the
  individual resulting in graft rejection
• The humoral antiBody system produces secreted
  antibodies (proteins) which bind to antigens and
  identify the antigen complex for destruction.
  Antibodies act on antigens in the serum and
  lymph. B-cell produced antibodies may either be
  attached to B-cell membranes or free in the serum
  and lymph.
• The cell mediaTed system acts on antigens
  appearing on the surface of individual cells.
  T-cells produce T-cell receptors which recognize
  specific antigens bound to the antigen presenting
  structures on the surface of the presenting cell.

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Humoral AntiBody System - B lymphocytes

• each B lymphocyte produces a distinct antibody
  molecule (immunoglobulin or Ig)
• over a million different B lymphocytes are
  produced in each individual
• thus, each individual can recognize over a
  million different antigens
• the antibody molecule is composed of 2 copies of
  2 different proteins
• there are two copies of a heavy chain - over 400
  amino acids long
• there are two copies of a light chain - over 200
  amino acids long
• each antibody molecule can bind 2 antigens at one
  time
• thus, a single antibody molecule can bind to 2
  viruses which leads to clumping

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• Classes determined by C terminal end of heavy
  chains
• IgM - multimeric, interact with complement, first
  response
• IgG - monomeric, long-lived, second response,
  secreted
• IgA - monomeric, long-lived, secreted in mucous
  surfaces
• IgE - monomeric, triggers inflammation in attacks
  by parasites, associated with allergies, binds to
  mast cells by C terminal end of heavy chains

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Antibody Diversity

• Each B cell produces identical antibodies
  specific to only one antigen.
• Millions of different antibodies can be produced
  - each produced by only one cell line.
• The nearly limitless diversity is achieved by the
  splicing of exons in the DNA as B cells mature.
• Light chain diversity (genes located on
  chromosomes 2 and 22) 100 V exons 4 J exons 10
  V-J joint combinations 4,000 total combinations
  
• Heavy chain diversity (gene located on chromosome
  14) 300 V exons 20 D exons 4 J exons 10 D-J
  and V-DJ joint combinations and 100 possible
  base insertions in joint 24 million
  combinations
• Combined diversity 4 x 103 light chains X 2.4 x
  107 heavy chains 9.6 x 1010

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Going to work

• As B cells mature, exon splicing creates a unique
  combination at a light chain gene and a heavy
  chain gene.
• This results in a B cell capable of producing a
  specific antibody before the antigen has been
  encountered.
• Virgin B cells display their antibodies on the
  cell surface in the form of IgM molecules.
• If an antigen is encountered which binds well to
  a B cell antibody, the antigen is engulfed and
  then presented on the cell surface in a MHCII
  marker.
• If a helper T cell recognizes the displayed
  antigen, the T cell induces the B cell to divide
  and differentiate antibody producing cells and
  memory cells.
• If no helper T cell recognizes the displayed
  antigen, the B cell is not stimulated and will
  eventually die. This guards against recognition
  of self or autoimmunity.
• B cell differentiation also involves Ig class
  switching from IgM to IgG or IgA.
• Antibody producing cells have a limited lifetime
  and the level of antibody production goes down
  over time.
• Memory B cells have a longer lifetime and allow
  for a quicker and more intense response to the
  next encounter with that antigen.

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Many of the endocrine pathologies are
multi-variant

• They often start out in one system and progress
  to others as one ages.

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Autoimmune Polyendocrine Syndromes

• APS-II (Autoimm Polyendocrine)
• APS-I (AIRE mutation)
• XPID (Scurfy Mutation)
• Anti-insulin Receptor Abs Lupus
• Hirata (Anti-insulin Autoantibodies)
• POEMS Congenital Rubella DM Thyroid
• (Plasmacytoma,..)
• Thymic Tumors Autoimmunity

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Polyendocrine non-Autoimmune Syndromes

• Wolframs Syndrome DIDMOADDiabetes Insipidus,
  Diabetes Mellitus, Optic Atrophy, and Deafness
  (WFS1 gene mutation on Chromosome 4)
• Kearns-Sayre SyndromeExternal Ophthalmoplegia,
  Retinal Degeneration, Heart Block- Diabetes,
  Hypoparathyroidism, Thyroiditis reported
  (Mitochondrial deletions, rearrangments)

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APS-Syndromes

• APS-Igt2 of Candidiasis, Hypopara,Addisons
• APS-IIAddisons Autoimmune Thyroid and/or Type
  1 Diabetes
• APS-III Thyroid Autoimmune other autoimmune
  not above
• APS-IV Two or more organ-specific autoimmune,
  not I,II, or III.

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Associated Autoimmune Illnesses
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Comparison APS-I and APS-II APS-I
APS-II

• Older Onset
• Multiple Generations
• DR3/4 Associated
• No Defined Immunodeficiency
• 20 Type 1 DM

• Onset Infancy
• SiblingsAIRE gene mutated
• Not HLA Associated
• ImmunodeficiencyAsplenismMucocutaneous
  Candidiasis
• 18 Type 1 DM

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APS-I

• Autoimmune Polyendocrine Syndrome Type 1
• Autosomal Recessive mutations AIRE (Autoimmune
  Regulator) gene
• Mucocutaneous Candidiasis/Addisons
  Disease/Hypoparathyroidism
• 18 Type 1 Diabetes
• Transcription Factor in Thymus

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Chronic mucocutaneous candidiasis

• Heterogeneous disorder of the immune system
  characterized by persistent candida (yeast)
  infections of the mucous membranes, scalp, skin
  and nails. Patients usually have problems with
  thrush (a yeast infection in the mouth) and yeast
  diaper rash as babies. Some patients also have
  problems with additional germs including bacteria
  and other fungi. Patients with mucocutaneous
  candidiasis have an increased incidence of
  autoimmune disorders including endocrine
  disorders, diabetes, hemolytic anemia, autoimmune
  hair loss (alopecia) or loss of skin pigment
  (vitiligo).

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• Clinical Features and Symptoms
• persistent candida (yeast) infections of the
  mucous membranes, scalp, skin and nails
• thrush (a yeast infection in the mouth) and yeast
  diaper rash as babies. 
• Some patients also have problems with
• additional germs including bacteria and other
  fungi. 
• increased incidence of autoimmune disorders
  including endocrine disorders, diabetes,
  hemolytic anemia, autoimmune hair loss (alopecia)
  or loss of skin pigment (vitiligo)
• Treatment Strategies
• Most patients with chronic mucocutaneous
  candidiasis are treated with chronic antibiotics
  that are specific for fungal infections. Patients
  should be evaluated periodically for endocrine
  disorders and those endocrine disorders should be
  treated as necessary.

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Unusual manifestations of disease APS-I

• Pituitary hormone deficiency (diabetes insipidus,
  growth hormone, gonoadotropic, ACTH deficiency)
• Autoimmune disease (hyperthyroidism, rheumatoid
  arthritis, Sjogrens syndrome, periodic fever
  with rash, antisperm autoimmunity, hemolytic
  anemia)
• Hemetologic manifestations (pure red cell
  aplasia, autoimmune hemolytic anemia,
  splenomegaly and pancytopenia, Ig A deficiency)
• Ocular disease (iridocyclitis, optic nerve
  atrophy, retinal degeneration)
• Other organ system involvement (nephritis,
  cholelithiasis, Bronchiolitis obliterans
  organizing pneumonia, Lymphocytic myocarditis)
• Hypokalemia with or without hypertension
• Metaphyseal dysostosis

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Immunodeficiency APS-I

• Live virus vaccination avoided
• If splenic atrophy present (Howell-Jolly bodies
  of blood smear, ultrasound)-Pneumococcal vaccine
  with Antibody response monitoring(6-8 weeks)-If
  no antibody response daily antibiotic prophylaxis

BDC
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Type II Syndrome Diseases
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Autoimmune Polyendocrine Syndrome Type II
(APS-II, Schmidts Syndrome)

• The type II syndrome is the most common
  autoimmune polyendocrine syndrome. In 1926,
  Schmidt described two subjects with thyroiditis
  and Addisons disease. Other diseases of the APS
  II include Graves disease (thyrotoxicosis),
  primary hypothyroidism, insulin-dependent or type
  1A diabetes mellitus (IDDM), celiac disease
  vitiligo serositis, IgA deficiency, primary
  hypogonadism, stiff-man syndrome, alopecia,
  pernicious anemia, myasthenia gravis, and
  Parkinsons disease. Organ-specific
  autoantibodies in the absence of overt disease is
  also frequently present in patients and their
  relatives.

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• Some authors divide the APS-II syndrome based
  upon the specific disease components reserving
  APS-II for Addisons disease plus autoimmune
  thyroid disease or type 1 diabetes (e.g. APS-III
  for thyroid autoimmunity plus other autoimmune
  (not Addisons or type 1 diabetes) APS-IV for
  two or more other organ specific autoimmune
  diseases). In that the additional divisions at
  present provide limited prognostic information
  (e.g. patient with diabetes and thyroiditis at
  risk for Addisons) we will use APS-II as
  inclusive of multiple autoimmune disorders with
  one or more autoimmune endocrine diseases but
  distinguished from APS-I with its unique triad of
  hypoparathyroidism, mucocutaneous candidiasis and
  Addisons disease and identified mutation of the
  AIRE gene

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APS II Environmental Factors

• Initiating factors for the type II syndrome and
  its component illnesses are not established
  except for celiac disease (wheat protein
  gliadin), the insulin autoimmune syndrome (e.g.
  methimizole), myasthenia gravis (rarely
  penicillamine, type 1A diabetes (rarely
  congenital rubella), Graves disease (rarely
  anti-CD52 monoclonal treating patients with
  multiple sclerosis) and hypothyroidism (rarely
  interferon).

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• Patients with celiac disease, which is
  characterized by atrophy of intestinal villi
  associated with lymphocytic infiltration, have
  autoantibodies reacting with transglutaminase
  (the endomysial antigen) and with less
  specificity and sensitivity with the wheat
  protein gliadin. Removal of gliadin from the diet
  restores intestinal villi to normal. In a similar
  manner, controversial data suggest that ingestion
  of the milk protein bovine albumin in the first
  few months of life may be associated with type 1
  diabetes while other investigators implicate
  casein, and recent studies from Denver and
  Germany (oral reports) implicate early (lt3
  months) ingestion of wheat. These dietary factors
  appear to increase risk of islet autoimmunity
  less than 2-3 fold. A number of drugs are
  associated with induction of autoimmunity
  including interferon-a (thyroiditis)(109).
  Remarkably , 1/3 of multiple sclerosis patients
  treated with an anti-CD52 monoclonal antibody
  developed Graves disease. Apparently
  non-multiple sclerosis patients treated with the
  same monoclonal do not develop Graves disease.

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Autoantibodies

• AutoantibodiesFamilies with the type II
  polyendocrine syndrome should be evaluated over
  time to detect the presence of organ-specific
  antibodies indicating the possibility of a future
  endocrine malfunction. All such relatives should
  be advised of the early symptoms and signs of the
  principal component diseases. Even though signs
  and symptoms of disease may be absent, patients
  with multiple disorders should be screened every
  few years with measurement of anti-islet
  antibodies, 21-hydroxylase autoantibodies and
  transglutaminase autoantibodies, a sensitive
  thyrotropin assay, and measurement of serum B12
  levels. ACTH and cosyntropin(adrenocorticotropin)-
  stimulated cortisol determination is indicated if
  21-hydroxylase autoantibodies are detected.
  Assays of anti-islet cell antibodies anti-thyroid
  and anti-adrenal antibodies(21-hydroxylase) and
  anti-ovarian antibodies help identify subjects at
  increased disease risk. An excellent autoantibody
  assay for celiac disease is now also available
  (determination of transglutaminase
  autoantibodies).

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• More than 20 years may elapse between the onset
  on one endocrinopathy and the diagnosis of the
  next. As many as 40-50 of subjects with
  Addisons disease will develop an associated
  endocrinopathy. A distinction must be made for
  subjects with isolated thyroid disease
  (relatively frequent in the general population)
  who have no family history of polyglandular
  syndrome type II. Such individuals have a
  relatively low probability of developing
  additional autoimmune disorders in comparison
  with individuals with rare autoimmune disorders
  such as Addisons disease or myasthenia gravis.
  Rarely, hypoparathyroidism, a specific endocrine
  disturbance present in the type 1 syndrome, is
  identified in a patient with type II syndrome.
  Hypoparathyroidism in such type II polyendocrine
  autoimmune patients may result from a
  suppressive autoantibody rather than
  parathyroid destruction as in the type 1
  syndrome. In a patient with the type II syndrome,
  celiac disease is a more frequent cause of
  hypocalcemia than hypoparathyroidism.

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• Several autoantibodies are both disease specific
  (e.g., anti-acetylcholine receptor antibodies in
  myasthenia gravis and anti-TSH receptor
  antibodies in Graves disease) and causal.
• Causal autoantibodies are associated with
  transplacental disease transmission. Other
  autoantibodies (e.g., antithyroid autoantibodies
  including anti-thyroid peroxidase, formerly
  termed anti-microsomal, and anti-thyroglobulin)
  are so frequent among patients and relatives as
  to be of little predictive value.
• For example, a relative with anti-thyroid
  peroxidase autoantibodies has a low risk of
  hypothyroidism unless evidence of abnormal
  thyroid function is also present (e.g., elevated
  TSH). In a similar manner, many individuals may
  have antibodies to parietal cells, H/K
  adenosine triphosphatase of the stomach and
  intrinsic factor, but the autoantibodies do not
  correlate well with abnormal gastric acid
  secretion or development of pernicious anemia.
  Studies of the neonatal presence of such
  autoantibodies will be important to determine if
  they increase risk of later disease.

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• In the APS-II syndrome, many ICA (islet cell
  antibody) -positive individuals do not progress
  to diabetes, and diabetes risk is much lower than
  for ICA-positive first-degree relatives of
  patients with type 1 diabetes. These
  non-progressing ICA-positive polyendocrine
  patients usually express what has been termed
  selective or restricted ICA. Such ICA react
  only with islet B cells, not A cells within rat
  islets and fail to react with mouse islets. They
  represent unusual high titer autoantibodies
  reacting with glutamic acid decarboxylase (GAD).
  This unusual form of ICA confers a lower risk of
  type 1 diabetes as compared with nonrestricted
  ICA (reacts with multiple islet molecules) for
  both polyendocrine patients and relatives of
  patients with type 1 diabetes.

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• Other autoantibodies associated with the type II
  syndrome include anti-melanocytic, anti-adrenal
  (in particular 21-hydroxylase) and anti-gonadal
  autoantibodies. Anti-adrenal cortical antibodies
  have been used to predict adrenal insufficiency
  in the type 1 syndrome.
• It is noteworthy that many of the polyendocrine
  autoantibodies react with intracellular enzymes,
  including thyroid peroxidase (Hashimotos
  thyroditis), glutamic acid decarboxylase (type 1
  diabetes and stiff-man syndrome), 21 hydroxylase
  (Addisons disease), and cytochrome P450
  cholesterol side chain cleavage enzyme (Addisons
  disease). In addition, antibodies to hormones can
  be present, including anti-insulin,
  anti-thyroxine, and anti-intrinsic factor
  antibodies (pernicious anemia).
• Antibodies to specific receptors are
  characteristic of given disorders
  (anti-acetylcholine receptor antibodies of
  myasthenia gravis, anti-TSH receptor antibodies
  of Graves disease or hypothyroidism, and oocyte
  sperm receptor autoantibodies associated with
  oophoritis). The large variety of target
  molecules, (e.g., type 1 diabetes), presence of
  high affinity IgG autoantibodies, and the
  sequential appearance over years of specific
  antibodies or disorders suggest that the
  production of most autoantibodies is secondary to
  tissue destruction and are antigen driven.

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Pathogenesis

• A central question is what links all the
  different disorders of the APS-II syndrome? Why
  do some individuals have a single autoimmune
  disorder while others have multiple diseases?One
  hypothesis is that different tissues share the
  same autoantigen and thus when autoimmunity is
  directed at one organ it will also affect other
  organs. This is highly unlikely given the number
  of different molecules targeted specifically for
  many autoimmune disorders and the wide
  discordance in time relative to the appearance of
  for instance specific autoantibodies and disease.
  Another hypothesis is that different organs may
  share immunologically related molecules (mimics)
  and such mimics may be as simple as short
  peptides recognized by T lymphocytes. That is
  also a possibility, but would not explain the
  wide time differences of disease appearance and
  spectrum of different illnesses. It is believed
  that the most likely link between the diverse
  diseases is genetic propensity to fail to
  maintain tolerance to multiple self molecules,
  and in particular specific self-peptides.

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• Environmental factors and additional genetic
  determinants (e.g. specific HLA alleles) then
  determine the timing of loss of tolerance and the
  probability that a specific organ will be
  targeted. Failure to maintain tolerance can be a
  result of deficient T regulation or enhanced T
  cell activation. An additional hypothesis is that
  HLA alleles associated with autoimmunity might be
  inherently contributing to autoreactivity. If
  this is true then specific HLA haplotypes can be
  protective for one autoimmune disorder and
  promote another.

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• For example DR2/DQB10602 haplotypes are high
  risk for multiple sclerosis but provide dominant
  protection for type 1A diabetes. Both
  autoreactive T cells and autoantibodies are
  pathogenic, depending on the specific disease. In
  Graves disease, anti-thyrotropin (TSH)
  autoantibodies lead to thyroid hyperfunction and
  anti-insulin receptor autoantibodies can result
  in either hypoglycemia or insulin resistance with
  hyperglycemia. Type 1A diabetes is a T cell
  mediated disorder and an interesting case report
  describes a child developing diabetes with a
  mutation eliminating B-lymphocytes and thus
  autoantibodies.T cell autoimmunity is much more
  difficult to study and correlate with a disease
  compared to autoantibodies.

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• Experimental animal models of organ-specific
  autoimmunity have been studied. These were
  dependent upon the injection of putative
  autoantigens into animals in the presence of
  adjuvants that enhance inflammation.
• Thus, thyroiditis can readily be induced in
  selective strains of mice following injection of
  thyroglobulin or thyroid peroxidase in Freunds
  adjuvant. Anti-insulin autoantibodies can be
  induced in normal Balb/c mice following the
  administration of insulin peptide B9-23, and
  these autoantibodies react with intact insulin
  and are not absorbed by the immunizing peptide.
• In Balb/c mice expressing an activating molecule
  in islets (B7.1) immunization with the B9-23
  peptide leads to diabetes. T cell clones reacting
  with these molecules, or other selected peptides,
  can be generated, and such clones when
  transferred into naive animals induce disease. Of
  note, several forms of immunization with such
  autoreactive clones can be used to make animals
  refractory to disease induction. These studies
  provide clear evidence that autoreactive T cells
  are present in normal animals and they can be
  rapidly activated, given appropriate
  stimulation.

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XPID (X-Linked Polyendocrinopathy, Immune
Dysfunction and Diarrhea)

• The XPID syndrome presents in neonates with fatal
  autoimmunity and this very rare disorder has
  multiple different names reflecting
  endocrinopathy, allergic manifestations,
  intestinal destruction and immune dysregulation .
• Most children with the disorder die in infancy
  and many die in the first days of life. They
  manifest neonatal type 1 diabetes, but the cause
  of death probably relates to massive intestinal
  involvement and malabsorption.The disease
  results from mutations that inactivate the Foxp3
  transcription factor and the same gene is also
  mutated in a mouse model (the Scurfy mouse). The
  pathway this gene controls in T lymphocytes is
  now identified as central to basic immunology. In
  particular the gene controls the regulatory
  function of CD4CD25 regulatory T
  lymphocytes(137178). From this discovery it is
  now apparent why bone marrow transplantation of
  normal lymphocytes is able to cure the mouse
  disease, namely the replacement of regulatory
  lymphocytes is able to control autoimmune
  reactivity of effector lymphocytes of the Scurfy
  mouse recipient, despite their lacking the Foxp3
  gene.

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Anti-Insulin Receptor Antibodies

• The presence of anti-insulin receptor
  autoantibodies is characterized by marked insulin
  resistance, but paradoxically, patients can also
  have severe hypoglycemia. Approximately one third
  of the subjects have other autoimmune disorders.
  Characteristically, associated autoimmune
  diseases are non-organ specific.

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Thymic Tumors

• Thymomas and thymic hyperplasia are associated
  with a series of autoimmune diseases. The most
  common autoimmune diseases are myasthenia gravis
  and red cell aplasia. Graves disease, type 1
  diabetes, and Addisons disease may also be
  associated with thymic tumors. Unique
  anti-acetylcholine receptor autoantibodies may be
  present with thymoma and disease may be initiated
  by transcription of molecules within the tumor
  related to acetylcholine receptors.

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POEMS Syndrome

• POEMS (Plasmacytoma, endocrinopathy, monoclonal
  gammopathy, and skin changes) patients usually
  present with a sensory motor polyneuropathy,
  diabetes mellitus (50), primary gonadal failure
  (70), and a plasma cell dyscrasia with sclerotic
  bony. T
• emporary remission may result following
  radiotherapy directed at the plasmacytoma. The
  syndrome is assumed to be secondary to
  circulating immunoglobulins but patients have
  excess vascular endothelial growth factor as well
  as elevated IL1-b, IL-6, and TNF-a.

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Insulin Autoimmune Syndrome (Hirata Syndrome)

• The insulin autoimmune syndrome, associated with
  Graves disease and methimazole therapy (or other
  sulfhydryl containing medications) is of
  particular interest due to a remarkably strong
  association with a specific HLA haplotype . Such
  patients with elevated titers of anti-insulin
  autoantibodies frequently present with
  hypoglycemia. The disease in Japan is essentially
  confined to DR4-positive individuals with
  DRB10406. In Hirata syndrome the anti-insulin
  autoantibodies are polyclonal. Some patients have
  monoclonal anti-insulin autoantibodies that also
  induce hypoglycemia. For these patients there is
  no HLA association with their disease.