title: Primary immunodeficiencies unravel critical aspects of the pathophysiology of autoimmunity and of the genetics of autoimmune disease.
abstract: BACKGROUND
  Primary Immunodeficiencies (PIDs) represent unique opportunities to understand the operation of the human immune system. Accordingly, PIDs associated with autoimmune manifestations provide insights into the pathophysiology of autoimmunity as well as into the genetics of autoimmune diseases (AID). Epidemiological data show that there are PIDs systematically associated with AID, such as immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), Omenn syndrome, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), autoimmune lymphoproliferative syndrome (ALPS), and C1q deficiency, while strong associations are seen with a handful of other deficits.
  
  
  CONCLUSIONS
  We interpret such stringent disease associations, together with a wealth of observations in experimental systems, as indicating first of all that natural tolerance to body components is an active, dominant process involving many of the components that ensure responsiveness, rather than, as previously believed, the result of the mere purge of autoreactivities. More precisely, it seems that deficits of Treg cell development, functions, numbers, and T cell receptor repertoire are among the main factors for autoimmunity pathogenesis in many (if not all) PIDs most frequently presenting with autoimmune features. Clearly, other pathophysiological mechanisms are also involved in autoimmunity, but these seem less critical in the process of self-tolerance. Comparing the clinical picture of IPEX cases with those, much less severe, of ALPS or APECED, provides some assessment of the relative importance of each set of mechanisms.
authors.affiliation: Instituto Gulbenkian de Ciência, Apartado 14, 2781-901 Oeiras, Portugal. coutinho@igc.gulbenkian.pt
authors.forename: Antonio
authors.initials: A
authors.lastname: Coutinho
authors.forename: Magda
authors.initials: M
authors.lastname: Carneiro-Sampaio
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D015551:Autoimmunity; D015922:Complement C1q / Q000172:deficiency / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D015322:Gene Rearrangement, B-Lymphocyte; D015329:Gene Rearrangement, T-Lymphocyte; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology*; D051379:Mice; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics; D011110:Polymorphism, Genetic; D017634:Self Tolerance / Q000235:genetics*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D000096927:AIRE Protein
chemical_list: D015922:Complement C1q; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D000096927:AIRE Protein; C418974:FOXP3 protein, human; C499311:RAG2 protein, human; C064658:RAG-1 protein