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Lecture_set_2.ppt Lecture_set_2.ppt Presentation Transcript

  • Lecture set 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.
  • 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.
  • 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?
  • 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.
  • 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 .
  • 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.
  •  
  • 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.
  • 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.
  • Components of the immune system
    • Made up of two cellular systems
    • humoral or circulating anti B ody system - B cells
    • cell media T ed 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 anti B ody 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 media T ed 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.
  •  
  • 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
    • 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
  • 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
  • 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.
  • Many of the endocrine pathologies are multi-variant
    • They often start out in one system and progress to others as one ages.
  • 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
  • Polyendocrine non-Autoimmune Syndromes
    • Wolfram’s Syndrome – DIDMOAD Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness (WFS1 gene mutation on Chromosome 4)
    • Kearns-Sayre Syndrome External Ophthalmoplegia, Retinal Degeneration, Heart Block- Diabetes, Hypoparathyroidism, Thyroiditis reported (Mitochondrial deletions, rearrangments)
  • APS-Syndromes
    • APS-I:>=2 of Candidiasis, Hypopara,Addison’s
    • APS-II:Addison’s + 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.
  • Associated Autoimmune Illnesses
  • Comparison APS-I and APS-II APS-I APS-II
    • Onset Infancy
    • Siblings AIRE gene mutated
    • Not HLA Associated
    • Immunodeficiency Asplenism Mucocutaneous Candidiasis
    • 18% Type 1 DM
    • Older Onset
    • Multiple Generations
    • DR3/4 Associated
    • No Defined Immunodeficiency
    • 20% Type 1 DM
  • APS-I
    • Autoimmune Polyendocrine Syndrome Type 1
    • Autosomal Recessive mutations AIRE (Autoimmune Regulator) gene
    • Mucocutaneous Candidiasis/Addison’s Disease/Hypoparathyroidism
    • 18% Type 1 Diabetes
    • “Transcription Factor” in Thymus
  • 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).
    • 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.
  • Unusual manifestations of disease – APS-I
    • Pituitary hormone deficiency (diabetes insipidus, growth hormone, gonoadotropic, ACTH deficiency)
    • Autoimmune disease (hyperthyroidism, rheumatoid arthritis, Sjogren’s 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
  • 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
  • Type II Syndrome Diseases
  • Autoimmune Polyendocrine Syndrome Type II (APS-II, Schmidt’s Syndrome)
    • The type II syndrome is the most common autoimmune polyendocrine syndrome. In 1926, Schmidt described two subjects with thyroiditis and Addison’s 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 Parkinson’s disease. Organ-specific autoantibodies in the absence of overt disease is also frequently present in patients and their relatives.
    • Some authors divide the APS-II syndrome based upon the specific disease components reserving APS-II for Addison’s disease plus autoimmune thyroid disease or type 1 diabetes (e.g. APS-III for thyroid autoimmunity plus other autoimmune (not Addison’s 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 Addison’s) 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 Addison’s disease and identified mutation of the AIRE gene
  • 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).
    • 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 (<3 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.
  • Autoantibodies
    • Autoantibodies Families 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).
    • 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 Addison’s 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 Addison’s 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.
    • 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.
    • 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.
    • 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 (Hashimoto’s thyroditis), glutamic acid decarboxylase (type 1 diabetes and stiff-man syndrome), 21 hydroxylase (Addison’s disease), and cytochrome P450 cholesterol side chain cleavage enzyme (Addison’s 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”.
  • 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.
    • 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.
    • For example DR2/DQB1*0602 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.
    • 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 Freund’s adjuvant. Anti-insulin autoantibodies can be induced in normal Balb/c mice following the administration of insulin peptide B:9-23, 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 B:9-23 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.
  • 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 CD4+CD25+ regulatory T lymphocytes(137;178). 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.
  • 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.
  • 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 Addison’s 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.
  • 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.
  • 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 DRB1*0406. 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.