IN PRIMARY IMMUNODEFICIENCIES APECED: Is this a model for failure of T-cell and B-cell tolerance? Nicolas Kluger, Annamari Ranki and Kai Krohn Journal Name: Frontiers in Immunology ISSN: 1664-3224 Article type: Review Article Received on: 24 Apr 2012 Accepted on: 15 Jul 2012 Provisional PDF published on: 15 Jul 2012 Frontiers website link: www.frontiersin.org Citation: Kluger N, Ranki A and Krohn K(2012) APECED: Is this a model for failure of T-cell and B-cell tolerance?. 3:232. doi:10.3389/fimmu.2012.00232 Article URL: http://www.frontiersin.org/Journal/Abstract.aspx?s=1244& name=primary%20immunodeficiencies&ART_DOI=10.3389 /fimmu.2012.00232 (If clicking on the link doesn't work, try copying and pasting it into your browser.) Copyright statement: © 2012 Kluger, Ranki and Krohn. 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Fully formatted PDF and full text (HTML) versions will be made available soon. 1 1 2 3 4 APECED: Is this a model for failure of T-cell and B-cell tolerance? 5 6 7 8 9 10 Nicolas Kluger1, Annamari Ranki1 and Kai Krohn2* 11 12 1Department of Dermatology, Allergology and Venereology, Institute of Clinical Medicine, 13 University of Helsinki, Skin and Allergy Hospital, Helsinki University Central Hospital, Helsinki, 14 Finland 2 15 Clinical Research Institute HUCH Ltd, Helsinki, Finland 16 17 18 19 20 *Corresponding author: Professor Kai Krohn, Salmentaantie 751, 36450 Salmentaka, Finland. E- 21 mail [email protected] 22 Phone number: +358-40-833 1366 23 Fax number: +358-9-4718 6500 24 25 Running title: APECED syndrome 26 27 Conflicts of interest: none declared 28 Grant support: The study was financially supported by the European Science Foundation (ESF) and 29 the Sigrid Juselius foundation (NK) 30 31 32 Word count: 6027 33 Figure :Figure: 1 34 Tables :Tables: 2 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 2 50 Abbreviations 51 AADC: aromatic L-amino acid decarboxylase 52 AD: Addison’s disease 53 AE: Autoimmune enteropathy 54 APS-1: Autoimmune polyendocrinopathy syndrome type 1 55 APECED: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy 56 CMC: chronic mucocutaneous candidiasis 57 EECs: enteroendocrine cells 58 GI: gastro-intestinal 59 HP: Hypoparathyroidism 60 IPEX: Immune dysregulation, polyendocrinopathy, enteropathy and X-linked 61 IF: Intrinsic factor 62 IL-1: Interleukin-1 63 IL-17: Interleukin-17 64 IL-22: Interleukin-22 65 mTECs: thymic medullary epithelial cells 66 NALP-5: NACHT leucine-rich-repeat protein 5 67 PE : promiscuous expression 68 PTH : parathormone 69 SLE: systemic lupus erythematosus 70 TH : tyrosine hydroxylase 71 TPH :tryptophan hydroxylase 72 TRIMs: tripartite motif-containing proteins 73 TSA : tissue specific antigens 74 3 75 Summary 76 In APECED, the key abnormality is in the T-cell defect that may lead to tissue destruction chiefly 77 in endocrine organs. Besides, APECED is characterized by high-titer antibodies against a wide 78 variety of cytokines, that could partly be responsible for the clinical symptoms during APECED, 79 mainly chronic mucocutaneous candidiasis, and linked to antibodies against Th17 cells effector 80 molecules, IL-17 and IL-22. On the other hand, the same antibodies, together with antibodies 81 against type I interferons may prevent the patients from other immunological diseases, such as 82 psoriasis and systemic lupus erythematous. The same effector Th17 cells, present in the 83 lymphocytic infiltrate of target organs of APECED, could be responsible for the tissue destruction. 84 Here again, the antibodies against the corresponding effector molecules, anti-IL-17 and anti-IL-22 85 could be protective. The occurrence of several effector mechanisms (CD4+ Th17 cell and CD8+ 86 CTL and the effector cytokines IL-17 and IL-22), and simultaneous existence of regulatory 87 mechanisms (CD4+ Treg and antibodies neutralizing the effect of the effector cytokines) may 88 explain the polymorphism of APECED. Almost all the patients develop the characteristic 89 manifestations of the complex, but temporal course and severity of the symptoms vary 90 considerably, even among siblings. The autoantibody profile does not correlate with the clinical 91 picture. One could speculate that a secondary homeostatic balance between the harmful effector 92 mechanisms, and the favorable regulatory mechanisms, finally define both the extent and severity 93 of the clinical condition in the AIRE defective individuals. The proposed hypothesis that in 94 APECED, in addition to strong tissue destructive mechanisms, a controlling regulatory mechanism 95 does exist, allow us to conclude that APECED could be treated, and even cured, with 96 immunological manipulation. 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 4 124 Synopsis 125 126 Autoimmune polyendocrinopathy syndrome type 1 (APS-1), also called APECED (Autoimmune 127 polyendocrinopathy-candidiasis-ectodermal dystrophy) is a recessively inherited monogenic 128 condition, caused by mutations in both alleles of the AIRE-gene (Autoimmune regulator). The 129 clinical hallmarks of APECED are sequentially erupting failures of endocrine organs, but other 130 manifestations, such as enamel dysgenics’, keratoconjuctivitis and asplenia occur as well. The 131 phenotype varies in individual patients as to the time course and severity of the symptoms. 132 133 AIRE is normally expressed in the medullary epithelial as well as dendritic cells in the thymus and 134 is thought to be responsible for the promiscuous expression (PE) of tissue specific antigens (TSA). 135 This process in turn would lead to the destruction of potentially auto-reactive T-cells and their 136 escape from this central tolerance mechanism into the periphery and their target organs. However, 137 recent findings have shed light for alternate mechanisms of action. In thymus, it has been proposed 138 that AIRE is responsible for the proper development and differentiation of medullary epithelial 139 cells, rather than being a transcription factor regulating the expression of TSAs. Furthermore, in 140 addition of thymus, AIRE expression can also be seen, although in very few number, in cells 141 derived from the two other germinal layers, mesoderm and ectoderm and AIRE protein can be seen 142 by immunofluorescence in some rare cells in peripheral lymphatic tissue and in the basal cells of 143 epidermis. This extra-thymic expression may be linked to the non-endocrine lesions seen in 144 APECED. 145 146 Finally, during the recent years, two new immunological mechanisms have been shown to operate 147 in APECED. The level of regulatory T-cells, characterized by the FOXP3 gene, is low in the 148 APECED patients. Furthermore, in addition to organ specific antibodies, APECED patients have 149 autoantibodies to a large series of different cytokines, the most frequently occurring being those 150 recognizing type 1 interferons and the product of Th17 cells, IL-17 and IL-22. Antibodies to the 151 last two are thought to be responsible for the chronic candidiasis, but in general, these cytokine 152 antibodies could also be protective, forming a balance mechanism to counter the effect of the 153 effector molecule. 154 155 In summary, both T-cell and B-cell products seem to be responsible for the various clinical signs 156 and symptoms in APECED. In an effort to balance these detrimental immunological mechanisms, 157 there seems to be again both T- and B-cell linked mechanisms, the regulatory T-cells and anti- 158 cytokine antibodies. 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 5 175 Introduction: 176 Autoimmune polyendocrinopathy syndrome, type 1 (APS-1) or autoimmune polyendocrinopathy– 177 candidiasis–ectodermal dystrophy syndrome (APECED; OMIM 240300) is a rare recessively 178 inherited disorder [1-4]. It is caused by mutations in the autoimmune regulator (AIRE) gene located 179 on locus 21q22.3 [5-7]. APECED displays a worldwide distribution, but specific clusters of high 180 prevalence of the disease are observed among Finns (1 : 25 000) [8] and Sardinians 1(1 : 14 500) 181 [9,10]. It is characterized by the variable association of autoimmune endocrine 182 (hypoparathyroidism, Addison’s disease, hypothyroidism, gonadal insufficiency, insulin-dependent 183 diabetes mellitus, atrophic gastritis and Biermer’s disease) and non-endocrine disorders (keratitis, 184 malabsorption, vitiligo, alopecia areata) and a specific predisposition to chronic mucocutaneous 185 candidiasis (CMC). A definite diagnosis of APECED is made upon one of the following criteria: i) 186 the presence of at least two of three major clinical features: CMC, hypoparathyroidism (HP) and 187 Addison's disease (AD), or ii) one disease component if a sibling has already a definite diagnosis or 188 iii) disease-causing mutations in both alleles of the AIRE gene. However, APECED being highly 189 variable in its presentation, the classical triad may be complete only after years of evolution and 190 diagnose may be therefore missed. Besides, APECED may appear during adolescence or in the 191 young adult [4]. Therefore, criteria for a probable APECED have been defined as follows: i) 192 presence of one of CMC, HP, AD (before 30 years of age) and at least one of the minor components 193 chronic diarrhea, keratitis, periodic rash with fever, severe constipation, autoimmune hepatitis, 194 vitiligo, alopecia, enamel hypoplasia, ii) any component and anti-interferon antibodies or iii) any 195 component and antibodies against NALP5 , AADC, TPH or TH [4]. 196 197 From circulating auto-immune antibodies to AIRE, FOXP3, APECED and IPEX 198 199 Our knowledge of the nature of the condition now called APS-1 or APECED has increased 200 simultaneously with the general development of immunology and autoimmunity.