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Kérdezz-felelek
nagyon köszönöm a gyors válaszát! A második kérdést nem sikerült egyértelműen feltennem, és bemásolnom sem, ahogy látom, a formázást nem vette be a rendszer. Megpróbálom újra.
Tehát az egyik cikk szerint az APS III-nál az AT (autoimmun thyr.) mellé társul az APS I-ből (candidiazis, Addison-kór, hypoparathyreosis, Diabetes mellitus) egy betegség. A másik cikkben viszont az APS vagy angolul TAD, ha jól értem, a következő csoportosulásokat alkotja:
Autoimmun pajzsmirigybetegsegek (TAD); (Hashimoto-thyreoiditis, Basedow–Graves-kor, Graves-orbitopathia)
TAD-3/A
(endokrin)
- IDDM
- Hirata-betegseg
- Hypophysitis
- Addison-kór
- Hypoparathyreosis
TAD-3/B
(gastrointestinalis)
- Autoimmun gastritis
- Anaemia perniciosa
- IBD
- Autoimmun hepatitis
- Primer biliaris cirrhosis
TAD-3/C
(hematologiai/bőr/idegrendszeri)
- Vitiligo
- Alopecia areata
- ITP
- Myasthenia gravis
- Sclerosis multiplex
TAD-3/D
(szisztemas-kollagen)
- MCTD
- RA
- SLE
- Sjögren-kór
- Vasculitis
Tehát a TAD3/C felelne meg az APS3/C-nek, de az itt szereplő betegségek nem egyeznek az APS1 már leírt betegésgeivel. A kérdésem, hogy ezek szerint az APS3-hoz ÉS/VAGY relációval kapcsolhatók az APS1 betegségei illetve az itt felsoroltak? Tehát vagy az egyik csoportosulás vagy a másik, vagy pedig mindegyik társul(hat)? Ugyanehhez kapcsolódóan, ezek a társulások megakadáloyzhatók, késleltethetők a kezeléssel, vagy a pajzsmirigy pusztulása (esetleg más egyéb) esetén előbb-utóbb kialakulnak? Ha nekem egyik sem áll fenn a TAD társulásokból, várható, hogy ezek közül valamelyik felbukkan?
Lehet, hogy nagyon nehéz kérdéseket tettem fel Önnek, de az a helyzet, hoyg sok mindent elolvastam már a témában - sorstársaimmal együtt -, de az ilyen jellegű kórképek alakulásáról és a betegség természetéről, várható viselkedéséről nem találtam egy írást sem. Pedig tudom másoktól is, hogy annak, aki ezzel küzd, rendkívül sokat jelente...
Segítségét és válaszát előre is köszönöm, üdvözlettel:
Edina
az APS és a TAD különböző fogalmak.
Nem tudok mást tenni, mint az ezzel kapcsolatos ( külföldi lapban megjelent közleményünket mellékelem.
Associations of Autoimmune Endocrine Diseases
Csaba Balázs MD1 and János Fehér MD2
1Department of Medicine, Hospital of the Order of Charity in Buda, Budapest
22nd Department of Medicine, Semmelweis University Medical School, Budapest, Hungary
Correspondonding address:
Csaba Balázs MD
1Department of Medicine, Hospital of the Order of Charity in Buda
Budapest
Frankel L. str. 4.
Hungary
E-mail: drbalazs@irgalmas.hu
Summary
Recently an increasing amount of data has been gathered on the connection between neuro-endocrine and immune systems. Results of molecular genetic research provided evidence for a common language of these systems including neurotransmitters, hormones and cytokines. It has been proven that the immune system is capable of producing neurotransmitters and hormones and even the endocrine system can prepare cytokines. This integrative (holistic) approach makes possible the investigation of physiological and pathological events as interactions of psycho-neuro-endocrine-immune systems. The associations of autoimmune diseases and the autoimmune polyendocrine syndromes constitute a heterogeneous group of disorders characterised by decreased or lost immune tolerance against self-antigens. Molecular genetic research explored the mechanism of the associations of diseases which are called organ-specific. Autoimmune polyendocrine syndrome Type 1 is characterised by the presence of at least two of the three cardinal diseases: Addison’s disease, autoimmune hypoparathyroidism, and mucocutaneous candidiasis. This rare autosomal recessive syndrome is induced by mutations of the autoimmune regulator (AIRE) gene. Autoimmune polyendocrine syndrome Type 2 that occurs at a much higher frequency is observed and defined as the coexistence of Addison’s disease, autoimmune thyroid disease and/or Type 1 diabetes mellitus. Autoimmune polyendocrine syndrome Type 3 is characterised by an association of autoimmune thyroid disease and Type 1 diabetes mellitus. In contrast to autoimmune polyendocrine syndrome Type 1, HLA and other antigens have proven to be important in Types 2 and 3 of the syndrome. Identification of genetic factors predisposing to these syndromes contributes to our understanding of the common mechanisms involved in autoimmunity and offers a possibility for early treatment and prevention as well.
Keywords: immunoendocrine diseases, associations of autoimmune diseases, immunoendocrine regulation, integrative medicine, polyendocrine autoimmune diseases
Abbreviations
ACTH = adrenocorticotrophic hormone
AIRE = autoimmune regulator gene
APECED = Autoimmune Poly-Endocrinopathy, Candidiasis, Ectodermic Dystrophy
APS = autoimmune polyendocrine syndrome
AT = autoimmune thyroiditis
CTLA-4 = cytotoxic T lymphocyte antigen 4
DC = dendritic cell
EMG = electromyogram
IBD = inflammatory bowel disease
IDDM = Type 1 diabetes mellitus
ITP = idiopathic thrombocytopenic purpura
LATS = Long Acting Thyroid Stimulator
MCTD = mixed connective tissue disease
MHC = Major Histocompatibility Complex
OS = Obese Strain (chicken)
POEMS = polyneuropathy, organomegaly, endocrinopathy, M-protein, skin lesions
RA = rheumatoid arthritis
SLE = systemic lupus erythematosus
SNP = single nucleotide polymorphism
TAD = thyroid-associated disease
Tg = thyroglobulin
TNF = tumour necrosis factor
TPO = thyroid peroxidase enzyme
TRAIL = TNF-related apoptosis-inducing ligands
TSH = thyroid stimulating hormone
The discovery of autoimmunity can be ranked among the most significant results of the medicine in the last fifty years. Clinical observations and experiments showed that a whole series of diseases previously thought as having no known origin (“idiopathic”) can be traced back to the abnormal function of the immune system. In 1956, as first, Roitt et al demonstrated antibodies in the sera of patients with Hashimoto’s thyroiditis which reacted with the thyroid gland [1]. Later a disease similar to Hashimoto’s thyroiditis could be induced in rabbits by administration of a thyroid extract. A new development in the study of Graves-Basedow disease was the discovery of an immune globulin, LATS (Long Acting Thyroid Stimulator) which later has proven to be an antibody against the TSH receptor and responsible for the hyperfunction of the thyroid [2, 3, 4, 5, 6]. In 1957 Witebsky and Rose have formulated the criteria of autoimmune diseases [5] (Table 1).
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A better knowledge of immune regulation and immune genetics promoted a closer understanding of the pathomechanism of autoimmune diseases. The immune system is constituted by a complicated network of cells linked to each other via multiple connections. The recognition of antigens is performed by monocytes, macrophages, and dendritic cells (DC). This recognition is a complex process including breakdown of substances taken up by the cells, analysis of the epitomes of cleaved compounds, and transfer of information obtained about them. In recognition and transfer (“presentation”) of antigens, molecules of the Major Histocompatibility Complex (MHC) have an important function. They forward the recognised information to thymus- and bursa-dependent cells (T and B lymphocytes). The former can also be divided into two subgroups, the Th1 (T helper-1) cells are responsible for the cellular immune reactions, while T2 (T helper-2) cells direct the humoral immune processes. T cells undergo division, so-called blastic transformation in the presence of activating substances (mitogens) and antigens. During this process they produce biologically active substances, a part of which may be cytotoxic. B lymphocytes exert their effect via antibodies which are different both in their structure and in their function. A part of the antibodies bind to own individual immunoglobulins (idiotype) and create the so-called idiotype-anti-idiotype network that has an important role in the main task of the immune system, preservation of individual integrity. Another part of the antibodies may be cytotoxic or may enhance or inhibit the function of the cells [6, 7, 8, 9, 10, 11]. Due to the pathologic immune regulation, the cells of the immune system recognise self-cells or parts with differing antigenicity (“epitopes”) as foreign. Depending on the extent of sharing of the epitopes by the individual organs, systemic or organ-specific autoimmune diseases may develop [11, 12, 13]. The most recent results of molecular biological research also revealed that these shared epitopes are present in the different organs to a various extent. This can explain the clinical experience showing that systemic lupus erythematosus (SLE) is often associated with other diseases formerly thought to be organ-specific. In the development of autoimmune processes, regulating T cells (Treg) have a determinant role [12, 14, 15, 16]. Peripheral CD4+ cells are known to express in 5 to 10% also Foxp3+, CTLA-4 (cytostatic T-lymphocyte antigen 4), and GITR (glucocorticoid-induced tumour necrosis factor receptor family-related receptor) molecules. It has been demonstrated by a growing number of studies that the pathological functioning of CD4+ CD25+ Treg cells plays a role in the development of a whole series of autoimmune diseases (SLE, autoimmune thyroiditis, Type 1A diabetes mellitus, autoimmune bowel diseases) [17, 18, 19]. It is also known that CD4+ CD25+ Treg cells Foxp3+ Treg are of decisive importance in the maintenance of the immunological tolerance of the organism, and in the prevention of autoimmune diseases [12, 19, 20, 21]. Thank to genetic research it has been elucidated that several genes may play a role in the inheritance of autoimmune diseases. Of these the role of MHC genes was discovered at first, and the recent studies also demonstrated the importance of genes located in various chromosomes including HLA II (6p), CTLA-4 (2q), Foxp3 (10p), and autoimmune regulator (AIRE) gene (21p) [22, 23, 24, 25]. However, epidemiological studies and observations on twins indicate that in addition to the genetic factors, both epigenetic and environmental factors are also decisive in the impairment of immune regulation and development of autoimmune diseases. A detailed analysis of these factors, however, would extend beyond the scope of this paper’s subject matter, and therefore we refer to literary data relating to it [26, 27, 28, 29]. A biological recognition of great importance of the last decade showed that the psycho-neuro-endocrine system and the immune system not only interact with each other but they use common biochemical signals as well. The solution of this common “language” has become possible with the help of the most recent advances of molecular biology and genetics. At present we do not know yet all details of this multifaceted interaction, but our current knowledge is already enough for declaring that not separated systems but an integrated psycho-neuro-endocrine-immune system is responsible for the preservation of the organism’s homeostasis [30, 31, 32]. The interactions of the immune system were attributed to substances produced by it, the lymphokines. In the recent years, however, it turned out that lymphokines are produced not only by the cells of the immune system but also by the cells of the neuro-endocrine system, and therefore today these information-forwarding substances are called cytokines. Cytokines are polypeptide type molecules which specifically bind to the receptors on the cells’ surface and modify their function. In contrast to the hormones, cytokines exert their effects mostly by a paracrine or autocrine way. It should be mentioned, however, that sometimes there are overlaps in the effects of hormones and cytokines. This means that cytokines can be detected in the peripheral circulation and they may behave like hormones (e.g. interleukin 6 stimulates the hypothalamo-pituitary axis most intensively), on the other hand there are hormones (e.g. prolactin, ACTH, TSH) which may act as cytokines in the tissues. The basic approach of holistic medicine means that it studies the physiological and pathological mechanisms of the organism as an integral whole. By solving the code of a language that integrates regulation in the human body, research has opened a new direction in medicine. Numerous examples for interactions between systems previously thought to be autonomic can be mentioned from everyday practice. Hormones (steroids, prolactin, hormones of the thyroid gland) influence the physiological and pathological function of the immune system, and monoclonal antibodies against cytokines are already suitable for curing endocrine diseases of autoimmune pathomechanism in the daily praxis [23]. The most recent results show that various areas in the brain co-ordinate the maturation and functioning of immune cells on different ways and the “homunculus” model created on the base of this indicates which cerebral areas direct the maturation and activation of immune system [26, 30, 31] (Figure 1).
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Theoretical and Clinical Fundamentals of the Association of Organ-Specific Autoimmune Endocrine Diseases
Hashimoto’s thyroiditis is a chronic inflammation where the destructive autoimmune (humoral and cellular) process injures the acinar cells of the thyroid and may result in development of hypothyroidism. The disease is a typical form of organ-specific autoimmune endocrinopathies where the presence of autoantibodies was demonstrated first time. It is important to understand the pathomechanism of the disease because it may serve as a base for the understanding of the development of other endocrinopathies of autoimmune origin. AT can be elicited not only experimentally, but it occurs also spontaneously. This model helped to obtain knowledge of immunologic and immunogenetic factors which are significant in the evolution of the disease. It succeeded to breed a strain from the Cornell chicken, the “Obese Strain” (OS chicken) where an illness similar to Hashimoto’s thyroiditis develops at the age of 8 to 10 weeks; the titre of anti-thyroid antibodies also increases and the animals become hypothyroid. In these animals the development of the symptoms of thyroiditis was hindered by neonatal bursectomy or administration of androgen hormone, and it was made earlier and more severe by thymectomy. It has also been revealed that the evolution of the disease is influenced by genetic factors as well. Locus B which codes the tissue antigens in chicken is determinant in the development of the disease as in animals of B1B1 and B1B4 genotype the lymphocytic infiltration of the thyroid is marked at the age of 6 to 10 weeks, and there is a concomitant elevation in the titre of anti-Tg antibodies. Animals with the B4B4 genotype, however, get the illness less frequently. In human AT it has been demonstrated that the damage of thyrocytes is a complex process consisting of several steps where, in addition to the immunologic, immunogenetic factors, also epigenetic and environmental factors play a role [6, 7] (Figure 2).
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In addition to Tg, several thyroidal antigens are known as having relevance in autoimmune pathomechanism. Thyroid peroxidase (TPO) enzyme, sodium iodine symporter (NIS) and anti-deiodinase antibodies also play a role in the inflammatory processes. Of the autoantibodies, anti-Tg antibodies are known to impair thyrocytes via their antibody-dependent cytotoxicity and anti-TPO antibodies are known to bind complement and have direct toxicity, while a part of them is also capable of inhibiting the TPO enzyme. The role of apoptosis induced by the autoimmune processes (Fas-Fas ligand) and biological mediators belonging to the TNF cytokine family and substances which bind them (ligands) (TRAIL = TNF-related apoptosis-inducing ligands) has been supported by a growing number of experimental data [32, 33, 34, 35]. The importance of genetic factors in AT has been underlined by data of literature demonstrating the familial accumulation of the disease [21]. Investigation of HLA antigens confirmed that ATs form groups which are different also genetically. Increases in the frequencies of HLA DR3 or HLA DR5 were found in Hashimoto’s thyroiditis or in post partum thyroiditis (PPT) and atrophic thyroiditis, respectively. It has been demonstrated that DR3 and DQ8 alleles are susceptible while DR2, DR4 and DQ6 alleles are resistant to the disease. The cytotoxic T-lymphocyte antigen 4 (CTLA-4) is known to be important in the development of immune tolerance as the CTLA-4 molecule inhibits T cell proliferation. Some alleles of the CTLA-4 gene (G49) indicate an increased susceptibility to the disease; however the question why AT is the autoimmune disease which develops cannot be answered yet. Therefore, in addition to the “common genes” responsible for autoimmunity, also thyroid-specific genes are sought for, of which primarily the Tg-specific ones seem to be important. It succeeded to find the gene of susceptibility to AT in the vicinity (8q24) of the locus of Tg gene (chromosome 8) and it also turned out that individual point mutations of Tg (SNPs) increase susceptibility to the disease to a varying extent. In addition to the genetic background, the so-called epigenetic factors have an increasing reason for them demonstrating that hereditary mechanisms not coded in DNA sequences are also responsible for which of the autoimmune diseases will develop in a given patient [10, 16, 23, 25, 26]. Based on the most recent observations on twins, we can accept as demonstrated that also environmental factors have a determinant role in the genesis of AT, i.e. in identical, monozygotic twins the genetic disposition was estimated to be only 46 to 89% [21, 22]. Of the environmental factors iodine has a determinant role, as it has also been demonstrated by the program of WHO against iodine deficiency, iodine supplementation has led not only to the prevention of congenital iodine-deficient state but also to an increase in the number of patients with AT. The thyroiditis-provoking effect of increased iodine intake was related partly to the elicited changes in the antigenicity of autoantigens (e.g. Tg), partly with an increased expression of autoantigens and antigen transfer. Viral and bacterial infections are supposed to be able to induce the disease, but this could not be demonstrated so far [22, 33]. Observations demonstrating associations between the individual diseases of autoimmune pathogenesis are important both from theoretical and practical aspect. The importance of the issue lies in the fact that until now only the abnormal functioning of the “immune response genes” was thought to be responsible for the development of autoimmune diseases. The study of autoimmune polyendocrine syndrome Type 1 (APS-1) revealed the existence of the so-called “autoimmune regulator” (AIRE) gene, the mutation or alleles of which are responsible for the specific associations of the diseases. This discovery started a trend in genomic research which looks for potential mutations also in the evolution of individual endocrinopathies. The previous opinion that autoimmune diseases were limited to one organ each has become outdated. Particular associations of systemic autoimmune diseases and organ-specific forms occur frequently, causing variety, diversity of diseases. Research of this group of diseases bears special practical significance because it calls the attention of the clinicians to the often different associations of individual diseases and by this way it makes the frequently thorny path to diagnosis and therapy easier. It is a characteristic example for the associations of autoimmune diseases when AT is either accompanied or followed by autoimmune gastritis, pernicious anaemia, Type 1 diabetes mellitus (IDDM), Addison’s disease or hypadrenia [33, 34, 35, 36].
Clinical Forms of Autoimmune Polyendocrine Syndrome (APS)
Autoimmune polyendocrine syndrome means the association of several endocrine diseases of autoimmune pathogenesis. Accordingly, the classification below has been accepted (Table 1).
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The first APS was described very probably by Addison yet in 1855, although he did not know that he found a specific group of diseases. Later, after the description of the individual entities, the current classification was recommended by Neufeld and Blizzard in 1980 [36, 37, 38]. These diseases were considered previously as “idiopathic” and the present classification could only be created after the recognition of autoimmunity. Elaboration and use of the criteria of Witebsky and Rose and then of Rose and Bona to endocrine diseases of autoimmune origin was fundamental for a better understanding of the condition’s nature [5, 6, 7, 39, 40, 41, 42, 43] (Table 2).
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Recognition of the endocrine background provided new information not only on the evolution of diseases but also on the causes of associations. Common cellular and humoral mechanisms against the shared epitopes are responsible for the more frequent associated occurrence of certain conditions.
APS-1
Definition: it means the association of at least two of the three diseases below (Table 3):
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The disease had also other known names previously. Of those the most frequently used was APECED (Autoimmune Poly-Endocrinopathy, Candidiasis, Ectodermic Dystrophy), or Whitaker’s syndrome. The disease begins in childhood; its first sign is chronic candidiasis followed by the signs of hypoparathyroidism and then Addison’s disease [36, 38, 43, 44]. In addition to the major symptoms, minor symptoms (vitiligo, alopecia areata, coeliac disease, autoimmune hepatitis, hypogonadism, malabsorption, diabetes mellitus, autoimmune thyroiditis, chronic atrophic gastritis) appear after the age of 20 years and form the very colourful spectrum of the disease [43, 44].
Epidemiology:
APS-1 is a rare disease. Its prevalence is extremely varying; it is 1:9,000 among Iranian Jews, 1:14,000 in Finland, 1:25,000 in Sardinia, 1:80,000 in Norway, and 1:200,000 in Northern Italy; the female/male ratio is 1.0:2.4 [36, 38, 45].
Symptoms:
In almost 100% of cases mucocutaneous chronic candidiasis (CC), poorly responding to treatment, can be detected and it presents itself already in childhood (Figure 3).
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Importantly, APS-1 underlies approximately 45% of cases of CC occurring in childhood. Tetany/hypoparathyroidism and Addison’s disease can be detected in 79% and 72% respectively. Other organ-specific conditions (gonadal hypofunction, vitiligo, pernicious anaemia, enamel hypoplasia, nail dystrophy, alopecia) are associated with the disease considerably less frequently. In forms with hypoparathyroidism malabsorption should also be thought of. The inflammation of oesophagus may be painful and it causes cicatrisation in a part of cases or it may induce an increase in the number of epithelial neoplasms. Chronic hypoparathyroidism manifests itself later, averagely in the age of 3 months to 15 years. The most characteristic clinical symptoms include neuromuscular disorders, signs of tetany, paraesthesia, hypotonia, and malabsorption. Chvostek’s sign (spasms at the area innervated by the facial nerve, the angle of the mouth is drawn aside and the eyelid contracts) can be elicited and the Trousseau sign (contraction of tetany occurring upon strangulation of the arm for approximately 3 to 5 minutes) is positive. Latent tetany can be revealed by EMG. Also further signs of hypocalcaemia (dry skin, thin hair, deformities of the nails) can be observed. The signs and symptoms of Addison’s disease present themselves in the postnatal age from 6 months to 40 years, and show no difference in comparison to the so-called monosystemic form that is independent of APS. The marked weakness, weight loss, hypotonia, fluid depletion and hypocalcaemic episodes are striking. Upon the effect of infection or physical and mental overload, the patient may come to a crisis. The most frequent gastrointestinal symptoms include diarrhoea, abdominal pain, nausea and vomiting. Increased pigmentation of the skin and mucous membranes (gingiva, mouth) can be observed (Figure 4).
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Pathomechanism:
A defect in the immune regulatory gene is responsible for the development of autoimmune processes. Autoantibodies are produced against individual organs and tissues, and fungal diseases develop because of impaired T cell function. The disease can already be studied in animal experimental models as well. These interesting experiments showed that autoantibodies to both hepatic tissue and adrenal tissue can be detected in the sera of mice with genetic defect at the age of a few weeks.
Genetics:
APS-1 is an autosomal recessive, monogenic hereditary disease that is not associated with HLA antigens. This also suggests that it is an independent entity which differs from other diseases of autoimmune pathogenesis. The AIRE (Auto-Immune Regulator) gene is located on the long arm of chromosome 21; it consists of 14 exons and has a size of 13 kb (Figure 5).
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This gene codes the AIRE protein that consists of 545 amino acids and controls the expression of tissue-specific substances in the thymus, i.e. it determines to which antigens immune tolerance develops. AIRE gene and its product protein are in a high concentration in thymic epithelial cells, in dendritic/antigen-presenting cells, but it has low concentrations in the spleen and in the peripheral mononuclear cells. Mutations, deletions and insertions of the AIRE gene are responsible for the development of the disease [45, 46, 47]. The first and the most important so far is R257X mutation that can be found in exon 6 and has been detected in 82% of patients in Finland. The mutations R139X and Y85C were observed most frequently in Sardinia and in Iranian Jews respectively. The genetic examination of our above presented patient and his/her parents showed a deletion of exon 8 (Figure 6).
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The autoimmune mechanism against the autoantigens is responsible for the development of minor signs and symptoms (Table 5).
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Diagnosis:
In the laboratory diagnostics of the disease characteristic ionic and hormonal alterations (hypocalcaemia, hyperphosphataemia, and low PTH levels) can be demonstrated. Cytotoxic antibodies can be found in the sera of 11 to 68% of patients, and autoantibodies against the parathyroid glands and the calcium sensor are also present in a part of them [37, 44, 47]. If the disease is suspected, genetic tests are also necessary in addition to the endocrinological and immunological examinations, and they are of prognostic value. The therapy of APS-1 has been established only partially and it bears many difficulties. In the majority of cases it is based on hormone replacement. To cure CC means a difficult task because of the impaired T cells and there is a high risk of recurrence even in a successful case. Ketoconazole therapy is successful in a part of cases, but it also creates a problem because it inhibits the production of cortisol and testosterone, thus it can deteriorate the already decreased adrenal function. Replacement of the lost or reduced hormone levels should be striven after. Signs and symptoms of tetany could be diminished significantly by the administration of calcium and Vitamin D derivatives (calcitriol, cholecalciferol, dihydrotachysterol) [45, 47]. In the treatment of autoimmune hepatitis, prednisolone and azathioprine are used, but their use is considerably limited by the immune deficient state. Until now the immunostimulant products have not normalised the impaired immune response. Studies with stem cells, although show promise, are currently yet in an experimental stage.
APS-2
The disease, previously designated by the name of Schmidt’s syndrome, is characterised by the association of Addison’s disease and Type 1 diabetes mellitus (IDDM)/or autoimmune thyroid disease. The most frequent symptom of the condition (present in 100% of patients) is Addison’s disease, while autoimmune thyroiditis (or Graves-Basedow disease) and IDDM can be found in 70% and 52% of patients respectively. The association of the leading two diseases can be modulated by other illnesses. The disease is 2 to 3 times more frequent in women [48]. The disease manifests itself at the age of 30 to 40 years. The clinical signs and symptoms are identical with those of the individual associated diseases.
Epidemiology:
The prevalence of the disease depends on the association of conditions examined. IDDM is associated with thyroid disease of autoimmune pathogenesis, pernicious anaemia or Addison’s disease in 5.7%, 0.5% and 0.1% respectively. At the same time IDDM could be diagnosed in 8 to 20% of patients with Addison’s disease. The incidence of APS-2 increases with advancing age [22, 36, 39, 41].
Genetics:
The disease is of autosomal dominant inheritance with incomplete penetrance. Research of the recent years has made it clear that, in contrast to APS-1, HLA antigens and their related immune response (IR) genes are decisive in this disease. This disease is significantly more frequent in people with a haplotype of HLA-DR3/HLA-DR4 [31]. Certain HLA haplotypes (DR3 DQA1*0501 DQB1*0202 DRB1*0301 and DR4 DQA1*0301 DQB1*0302 DRB1*0401) significantly increase the risk of the disease, while others (HLA DR6 DQA1*DQB1*0503 DRB1*1401) have a protective effect [10, 31]. Tumour necrosis factor (TNF) and cytotoxic T-lymphocyte 4 (CTLA-4) genes, which are associated with HLA genes, have been shown to be important in the development and inheritance of the disease [33, 48]. The substantial differences between APS-1 and APS-2 are summarised in Table 6.
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APS-3
This disease was originally defined by Neufeld as an association of Hashimoto’s thyroiditis, Graves-Basedow disease, Graves’ orbitopathy, praetibial myxoedema, and one of the autoimmune diseases below [38]:
• IDDM
• atrophic gastritis
• pernicious anaemia
• vitiligo
• alopecia
• myasthenia gravis.
It turned out, however, that this group of diseases is considerably more complex, as the autoimmune disease of the thyroid (TAD = thyroid-associated disease) was associated with other autoimmune conditions in 28%, including Sjögren’s disease, coeliac disease, myasthenia or SLE. It has been observed that several autoimmune diseases were present in an incomplete form in more than half of patients with TAD. As patients with TAD amount to 7 to 8% of the population, therefore a new classification was made with the essentials that it is suitable for classifying both overt and subclinical diseases [29, 33, 36, 38, 49]. (Table 7).
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Differential Diagnosis of APS
Regarding the different associations of entities observed in the individual forms of APS, difficulties may emerge in differential diagnosis. Of the diseases of chromosomal origin, Turner syndrome may cause a diagnostic problem, as autoimmune thyroiditis (in 30%) and other endocrinopathies may also occur in this disease. In Kearns-Sayre syndrome hypoparathyroidism, primary hypogonadism, IDDM, and hypopituitarism can be observed as well, however myopathy is in the foreground of the disease. Wolfram syndrome (diabetes mellitus, diabetes insipidus, optic atrophy, neural hearing loss) is a rare congenital disease which begins already in childhood. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M proteins and skin lesions) may cause diagnostic difficulty in adults. The abnormity of plasma cells and the appearance of M gradient may help in the diagnosis [49].
Diagnostic Protocol
Clinical picture/course is determinant in diagnostics. Laboratory data, however, may help in the early recognition of the diseases. The following tests are recommended: TPO, Tg, TSH-R GAD65, 17-hydroxylase and 21-hydroxylase antibodies. The presence of M gradient or the absence of IgA may be detected by quantitative immunoelectrophoresis. Determination and follow-up of the levels of target organ hormones is essential not only for the diagnosis but also for monitoring the appropriateness of therapy.
Therapy, Care
The treatment is founded on influencing the abnormal function of immune system, improving the impaired functions, and replacing the deficient hormones. Based on the pathomechanism, we should (possibly) strive for termination of autoimmunity. This problem has been solved only in part yet. By the intake of hormones (e.g. thyroid hormones, insulin) we reduce the expression of HLA-DR molecules on the surface of target organs’ cells and mitigate the autoimmune process. The essence of this so-called isohormonal therapy can be understood the best during treatment of autoimmune thyroiditis. TSH can enhance the expression of HLA-DR molecules, thus the timely T4 and T3 therapy means, by reducing TSH levels, not only replacement of the hormones but it also inhibits the autoimmune process. Products inhibiting thyroid function play a role not only in the development of euthyroidism, but by inhibiting the autoantigens, they also inhibit the autoimmune process. Timely insulin therapy also inhibits the expression of HLA-DR expression of beta cells, and restrains the destruction of the cells. For the other part of hormone replacement therapies no immunomodulating effects have been demonstrated (e.g. increased intake of Vitamin D used in hypoparathyroidism). The importance of patient care and prevention follows from the foregoing.
Life expectancies of patients may improve by appropriate and life-long care, one of the main elements of this is informing the patients about the nature of their disease and that the administered medication has to be modified inevitably in certain stressful situations. At an appropriate hormonal therapy women who were previously infertile can give birth to children, however closer supervision is required during pregnancy and after delivery. The objective and at the same time result of care implies that patients’ life expectancies should not worsen, on the other hand their quality of life should allow them, after having chosen an appropriate work, to live a life of full value [49].
Literature:
[1] Roitt, I.M., Doniach,D., Cambell, P.N. et al.: autoantibodies in Hashimoto’s thyroiditis. Lancet, 1956, 2, 820-824.
[2] Rose, N. R., Witebsky,E.: Studies in organ specificity. Changes in the thyroid glands of rabbits following active immunization with rabbit thyroid extracts. J. Immunol. 1956, 76, 417-427.
[3] Adams, D.D., Purves, H.D.: Abnormal response in the assay of thyrotropin. Proc. Univ. Otago Med. School 1956, 32, 11-12.
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Correspondonding address:
Csaba Balázs MD
1Department of Medicine, Hospital of the Order of Charity in Buda
Budapest
Frankel L. str. 4.
Hungary
E-mail: drbalazs@irgalmas.hu
List and Explanation of Figures
Figures:
Figure 1 Major Sites of Regulation of the Immune System in the Central
Nervous System
Figure 2 Outline of the Pathomechanism of Autoimmune Thyroiditis
Figure 3 Signs of Mucocutaneous Candidiasis on the Oral Mucosa of a
Patient with APS-1
Figure 4 Increased Gingival Pigmentation and Enamel Hypoplasia in a
Patient with APS-1
Figure 5 Localisation of the APS-1 Gene (Red Line)
Figure 6 Examination of 8.13 bp Deletion of the AIRE gene
1. Marker of Molecular Weight
2. Homozygous Patient with APS-1 (13 bp Deletion)
3. Heterozygous Father of the Patient with APS-1
4. Heterozygous Mother of the Patient with APS-1
5. Healthy Control
Table 1
Classification of APS
• APS-1: Candidiasis, hypoparathyroidism, Addison’s disease
• APS-2: Addison’s disease + autoimmune thyroid disease and/or Type 1 diabetes mellitus
• APS-3: Autoimmune thyroid disease + one of the above mentioned diseases
Table 2
Evidences of Autoimmune Disease
• Direct Evidence(s): passive transfer of the disease with autoantibodies or autoreactive T cells
• Indirect Evidence: reproduction of the disease under experimental conditions
• Secondary Evidence(s): lymphocytic infiltration in the target organ, association with another autoimmune disease, correlation with HLA antigens, beneficial therapeutic effect of immunoregulation
Table 3
Major Components of APS-1
• Chronic Mucocutaneous Candidiasis (manifesting at the age of about 5 years)
• Chronic Hypoparathyroidism (paraesthesia, Chvostek-Trousseau signs, EMG signs, dry skin, nail deformities)
• Addison’s Disease (at the age between 6 month and 40 years, mean: 14.6 years)
(hyperpigmentation, hypoglycaemia, weight loss, adynamia, hypotonia, diarrhoea, nausea – coma)
Table 4
Immunological Background of Major APS-1 Symptoms
• Candidiasis: primary T cell immunodeficiency
• Hypoparathyroidism: anti-parathyroid antibodies, anti Ca sensor antibodies
• Addison’s Disease: anti-adrenal cortex antibodies (ACA), anti-21 hydroxylase antibodies
Table 5
Minor APS-1 Symptoms and Antibodies against Autoantigens
Responsible for its Development
• Vitiligo
o melanocyte antigen
• Coeliac Disease
o reticulin, endomysium antigen
• Hypogonadism
o steroid-producing cells
o 17-hydroxylase enzyme antigen
o P450 scc antigen
• Autoimmune Hepatitis
o L-K microsomal antigen
• Type 1 Diabetes Mellitus
o ICA (islet cell antigen)
o GAD (glutamate decarboxylase enzyme)
o IA2 antigen
• Autoimmune Thyroiditis
o TPO (thyroid peroxydase enzyme)
o Tg (thyroglobulin)
• Chronic Atrophic Gastritis
o parietal cells
o H/K ATP-ase enzyme
o intrinsic factor
• Alopecia Areata
o tyrosine hydroxylase
• Malabsorption
o tryptophan
Table 6
Most Important Differences between APS-1 and APS-2
APS-1 APS-2
Beginning in childhood Beginning in adulthood
AIRE gene mutation detectable No AIRE gene mutation
No association with HLA Associated with HLA DR3/4
Immune deficiency detectable No evidence of immune deficiency
Mucocutaneous candidiasis No mucocutaneous candidiasis
Table 7
Classification of the Diseases Associated with Autoimmune
Thyroid Diseases (TAD)
Autoimmune Diseases of the Thyroid (TAD)
(Hashimoto’s thyroiditis, Graves-Basedow disease, Graves’ orbitopathy)
+
IDDM Autoimmune gastritis Vitiligo MCTD
Hirata disease Pernicious anaemia Alopecia areata RA
Hypophysitis IBD ITP SLE
Addison’s disease Autoimmune hepatitis Myasthenia gravis Sjögren’s disease
Hypoparathyroidism Primary biliary cirrhosis Multiple sclerosis Vasculitis
TAD-3/A TAD-3/B TAD-3/C TAD-3/D
(endocrine) (gastrointestinal) (haematological/ (systemic-collagen)
dermal/neural)
Figure 1
Early cytokine release
Clonal expansion
Activation of memory B cells
Late cytokine release
DC maturation
T cell maturation
Cholinergic anti-inflammatory regulation
Sensory
Visual
Auditory
Gustatory
Olfactory
Motor
Figure 2
Genetic predisposition
Environmental factors
(iodine, infections, pregnancy,
cytokine therapy)
Loss of immunological tolerance
Accumulation of autoreactive T cells (Th and Tc) and
autoantibody-producing B lymphocytes
in the thyroid gland, destruction of its tissue
Apoptosis
HYPOTHYROIDISM
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6.
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