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Primary biliary cirrhosis: does X mark the spot?
Autoimmunity Reviews 3 (2004) 493 – 499 www.elsevier.com/locate/autrev
Primary biliary cirrhosis: does X mark the spot? Carlo Selmi a,b,1, Pietro Invernizzi b,1, Monica Miozzo c, Mauro Podda b, M. Eric Gershwin a,* a
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, TB 192 One Shields Ave., Davis, CA 95616, USA b Division of Internal Medicine, San Paolo School of Medicine, University of Milan, Milan, Italy c Department of Medicine, Surgery and Dentistry, Laboratory of Human Genetics, San Paolo School of Medicine, University of Milan, Milan, Italy Received 17 March 2004; accepted 20 May 2004 Available online 25 June 2004
Abstract Primary biliary cirrhosis (PBC) is an autoimmune disease of unknown etiology leading to progressive destruction of intrahepatic bile duct, with cholestasis, cirrhosis, and eventually liver failure. Epidemiological data indicate that environmental factors trigger autoimmunity in genetically susceptible individuals, although no definitive association of PBC with specific genes has been found. Further, no convincing explanation has been provided for the strong female predominance observed in the prevalence of PBC. However, we recently suggested that the enhanced monosomy X in peripheral white blood cells, and particularly in lymphocytes, of affected women might play a role in the induction of PBC. Such observations appear independent from the degree of cholestasis and specific for PBC. In this review we discuss the implications of these findings and their immunological implications. D 2004 Published by Elsevier B.V. Keywords: Primary biliary cirrhosis; Female precominance; Monosomy X
Contents
1. Introduction . . . . . . . . . . . . . . . . . 2. Female predominance in PBC . . . . . . . . 3. The X Chromosome and the immune system 4. Monosomy X in PBC . . . . . . . . . . . . 5. Possible scenarios and concluding remarks . Take – home messages . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .
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* Corresponding author. Tel.: +1-530-752-2884; fax: +1-530-752-4669. E-mail address: [email protected] (M.E. Gershwin). 1 These authors equally contributed to this work. 1568-9972/$ - see front matter D 2004 Published by Elsevier B.V. doi:10.1016/j.autrev.2004.05.003
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C. Selmi et al. / Autoimmunity Reviews 3 (2004) 493–499
1. Introduction
Table 2 Sex ratios in PBC [37]
Primary biliary cirrhosis (PBC) has been an enigmatic disorder and unusual from the genetic perspective of the major histocompatibility complex (MHC) compared to other human autoimmune diseases [1]. Although the etiopathogenesis of human autoimmunity remains somehow enigmatic, we note that the majority of other immune mediated diseases have associations with genes or gene complexes within the major histocompatibility complex (MHC) [2]. In the case of PBC, such associations have been far less convincing [3]. However, the concordance of PBC between monozygotic twins [4] is higher when compared to other autoimmune diseases (Table 1). Nonetheless, PBC shares a number of features with other autoimmune diseases, including the presence of high titer autoantibodies against intracytoplasmic antigens, cell mediated responses against the same antigens, chronic inflammation, and a female predominance [5]. This latter observation has not been explained although a role for estrogens has been proposed. These features have led to the proposition that autoimmunity in PBC is produced by an environmental trigger, i.e. infection [6] or chemical xenobiotics [7], in a genetically predisposed individual [3]. Herein we present recent data on a role of specific X chromosome defects in
Year
Location
N of cases
M/F ratio
1983 1984 1984 1985 1990 1990 1995 1995 1997 2000
Newcastle, UK Malmoe, Sweden Western Europe Orebro, Sweden Ontario, Canada Northern England Victoria, Australia Estonia Newcastle, UK Olmsted county, MN (USA)
117 33 569 18 225 347 84 69 160 46
1:14 1:3 1:10 1:3.5 1:13 1:9 1:11 1:22 1:10 1:8
Table 1 Pairwise concordance rates of autoimmune disease in monozygotic and dizygotic twins (n of concordant sets/n of studied sets) (modified from Ref. [4])
Primary biliary cirrhosis Primary sclerosing cholangitis Systemic lupus erythematous Sjo¨gren’s syndrome Type I diabetes mellitus Rheumatoid arthritis Graves’ disease Multiple sclerosis Celiac disease
Monozygotic twins concordance rate
Dizygotic twins concordance rate
0.63 Concordant pair reported 0.24
0.00
Concordant pair reported 0.21 – 0.70a 12.3 – 15.4 0.17 – 0.29 0.25 – 0.31a 0.75 – 0.83
– 0.02
the induction of PBC and discuss the immunological implications.
2. Female predominance in PBC As observed for most autoimmune diseases, affected women, especially those of middle age, outnumber men by as much as 10:1 among PBC cases, although such ratio varies widely in different epidemiological studies (Table 2). Previous evidence once suggested that the natural history of PBC differs in males and females, with early onset asymptomatic PBC more common among men, accompanied by symptoms often not as severe as those seen in women. These data, however, have not been confirmed [8]. Sex hormones and their effects on the immune system have been often suggested as responsible for the female predominance in PBC. Nonetheless, data on sex hormones levels and metabolism in PBC have shown that the observed changes might be secondary to long-standing cholestasis [9]. One case-control study evaluated differences in reproductive history between women with PBC and matched controls using standardized questions and PBC cases had significantly more pregnancies than controls [10].
–
3. The X chromosome and the immune system 0.00 – 0.13 3.5 – 3.6 0.00 – 0.02 0.03 – 4.7 0.11
a Concordance rate following a minimum of 7.5 years of observation.
The biology of the X chromosome is unique, as there are two X chromosomes in females and only one copy in male individuals [11]. In mammals, X chromosome inactivation is the process that transcriptionally silences one of the two X chromosomes in
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females to compensate for the double dosage of Xlinked genes compared to males. In this process, maternal or paternal X chromosomes are randomly and independently inactivated in each cell, with an approximate 1:1 final ratio [12]. It has been postulated that females with autoimmunity may be particularly prone to a mechanism of ‘‘inadequate tolerization’’ by virtue of extremely skewed X chromosome inactivation [13]. In particular, an extreme skewing towards a single parental X chromosome may result in a situation in which polymorphic self-antigens on one X chromosome may fail to be expressed at sufficiently high levels in a tolerizing compartment, such as thymus, and yet may be expressed at a considerable frequency in the peripheral soma. Thus, women may be predisposed to a situation in which they can occasionally express X-linked autoantigens in the periphery to which they have been insufficiently tolerized. However, significant evidence has been raised discrediting this hypothesis [14]. A considerable number of sex- and immune-related genes have been mapped to the X chromosome; such genes appear crucial in the maintenance of physiological sex hormone levels and, more importantly, of immune tolerance, respectively. Monosomy or structural abnormalities of the X chromosome are present in genetic disorders such as Turner’s syndrome [15] or premature ovarian failure [16], often presenting accompanying autoimmune features. Moreover, we note that mutations in specific Xchromosome genes cause immunodeficiency syndromes characterized by different degrees of severity [17]. Finally, various X chromosome disorders can also be accompanied by signs of chronic cholestasis [15]. For these reasons, we hypothesized that X chromosome defects may play a role in the female preponderance of autoimmune diseases through alterations in the immune response.
4. Monosomy X in PBC X chromosomes may be an important determinant for the increased prevalence of PBC in women. While it cannot be excluded that sex hormones play a regulatory role in the natural history of PBC, the high number of sex- and reproduction-related genes on the
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human X chromosome [18] points towards defects of the X chromosome as more likely determinants for the altered sex ratio in the susceptibility to PBC. We have recently investigated the frequency of X chromosome monosomy in peripheral blood cells of 100 women with PBC and 100 age-matched women using fluorescent in situ hybridization [19]. We reported an enhanced monosomy X, that is a major defect of the X chromosome, in the peripheral blood cells of women with PBC, compared to controls. We also found that in PBC T and B lymphocytes presented this abnormality more frequently than other white blood cells. As previous reports indicated an age-dependent loss of the X chromosome in healthy adults [20], we also investigated monosomy X rates in 2 age-matched control groups composed of 50 healthy women and 50 women with chronic hepatitis C. The latter control group was also matched to patients with PBC for severity of disease. Finally, monosomy X was similar in PBC patients with and without cholestasis. Our results confirmed previously observed monosomy X rates in both control groups, thus ruling out a confounding effect of both age, altered liver function and cholestasis per se. Based on these data, we therefore suggested that a progressively acquired haploinsufficiency for specific X-linked genes may be involved in the etiopathogenesis of PBC, possibly through an instability of the X chromosome. Interestingly, the fact that monosomy X is more common in T and B cells than in other peripheral white blood cell subpopulations, suggests an explanation for the altered adaptive immune response demonstrated in PBC [21]. Although the molecular mechanisms are largely unknown, a progressive alteration of centromere function due to either faulty kinetochore proteins or premature centromere division can be hypothesized [22]. Alternatively, an accelerated aging process of involved cells may also be involved, likely due to the accumulation of subsequent errors in control mechanisms. As white cells in general and lymphocytes in particular are among the most mitotically active tissues of the body, they may also contain an increased frequency of such mitotic errors. Moreover, the rate of monosomic peripheral lymphocytes may indicate a larger cell population with micro-defects of the X chromosome, eventually associated with phenotypical changes. We also note that exposure to chemical and physical genotoxins can lead to loss of sex chromo-
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somes in peripheral blood cells [23]; such observations appear interesting in light of recent data suggesting a major role for chemicals (i.e. xenobiotics) in the onset of PBC [7]. Finally, we cannot rule out the possibility that the enhanced monosomy X may result from inheritance, as indirectly suggested by the strong genetic component encountered in PBC susceptibility [4]. The striking gender bias in incidence of PBC, together with the occurrence of X monosomy, prompted us to put forward a few hypotheses on the role that X-linked gene defects could play in PBC susceptibility. The search for X-linked candidate genes must consider that X chromosome in females is subjected to inactivation, to resolve X chromosome dosage between genders. The previously described mechanism of dosage compensation makes the genetically inherited monosomy X compatible with life, although with typical stigmata of Turner’s syndrome [15]. The impact of monosomy X on Turner’s syndrome phenotype has been attributed to the dosage deficiency of genes on the X chromosome which are normally expressed from both copies and are supplemented by functionally equivalent Y-linked homologous genes in male subjects [15]. A similar mechanism appears responsible for other female complex genetic disorders characterized by absence or by structural abnormality of the X chromosome [16]. Interestingly, a large number (up to 30%) of the X-linked genes have been recently shown to escape inactivation [24]. This appears interesting as the higher escape rate observed on the X chromosome may lead to increased frequency of disorders related to haploinsufficiency of specific genes. However, it is to note that although most of the X-linked genes escaping inactivation retain Y homologues and are located at PAR regions (Fig. 1), escape from silencing involves also genes outside PARs and not showing Y homologues. Because also males can develop PBC, in case of genes with homologue on Y chromosome, affected males have to display Y chromosome loss resulting in halfdosage of the putative genes. Alternatively, by considering genes escaping inactivation without evidence of a Y chromosome copy of the gene, i.e. EIF2S3, Y chromosome loss in affected males has not to be expected. In the future, it will be important to investigate whether sex chromosomes instability is present also in male patients with PBC, that is whether an Y
Fig. 1. Schematic G-banded representation of the human sex chromosomes. PAR1 and PAR2 (pseudoautosomal regions) indicate the main regions of homology between the sex chromosomes. On the left, genes discussed in the text as candidates for PBC development are shown (*indicates genes escaping X inactivation).
chromosome loss is more frequent in PBC male than in the healthy population. It seems interesting to note that, similarly to what described for X chromosome, an age-dependent loss of the Y chromosome has also been reported in healthy men [22]. It can also be hypothesized that the preferential loss of one of the two X chromosomes might unmask X-linked recessive mutations or polymorphisms. In this case, we have to presume that monosomy X preferentially involve one of the two X chromosome homologues. In addition, we have to presume that specific Y-linked genes exert a protective effect on X males. Indeed, being males constitutively hemizygous for the polymorphism, they would be more prone to PBC development than females. Futher, female carriers of certain X-linked immunodeficiencies provide hints to clarify the causes and implications of our findings. A progressive age-dependent nonrandom X inactivation [12] has been supposed to lead to the expression of recessive traits [25]. Similarly, it is possible that the clinical manifes-
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tations (or phenotype) of PBC might correlate with the amount of peripheral lymphocytes presenting insufficient expression of specific X-linked genes. Finally, the scenario is even more complex as recent studies point to individuality and variation in gene expression pattern in blood, mostly due to gender [26]. In addition, it has been reported that X-inactivation profile varies among female population [27]. Accordingly, future studies aimed to investigate genetic profile of candidate genes in PBC population must take into account also the peculiarity of X-linked genes expression profile in female population.
5. Possible scenarios and concluding remarks Based on our findings, we hypothesize two possible genetic models providing a connection between PBC and the candidate genes that future molecular studies of X chromosome abnormalities may identify. First, a polygenic model with an Xlinked major locus of susceptibility is suggested, with genes escaping X chromosome inactivation as the major candidates. Possible candidate genes include ANT3, escaping inactivation and also active on Y homologue, coding for the ADP/ATP mitochondrial carrier of liver [28], and several genes of the H – Y minor histocompatibility antigen [29]. Second, we hypothesize a multigenic complex inheritance model in which Y chromosome genes might exert a protective role, in case of preferential X chromosome loss or of skewed X inactivation that unmask X-linked recessive mutations or polymorphisms. A possible candidate gene could be JM2/FOXP3, involved in the pathogenesis of the X-linked-allergic dysregulation syndrome and the syndrome of immunodysregulation, polyendocrinopathy, and enteropathy (XLAAD, MIM: 304790) [30]. Similarly, the pyruvate dehydrogenase E1-alpha gene (PDHA1) [31] should also be considered. Interestingly, PDHA1 is one of the enzymatic components of pyruvate dehydrogenase complex family, the wellknown autoantigens of PBC-specific AMA [32]. Other genes mapping on the X chromosome, such as GP91-PHOX gene, also appear interesting. Mutations of GP91-PHOX, in fact, cause the X-linked chronic granulomatous disease (CGD, MIM:
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#306400), characterized by recurrent bacterial and fungal infections, as well as formation of granulomas [33]. Intriguingly, liver epithelioid granulomas are found in up to 80% of patients with PBC, but seldom in other hepatobiliary diseases, with the exception of sarcoidosis and tubercolosis [34]. Finally, the CD40 ligand (CD40L) gene is known to induce, through mutations, an X-linked immunodeficiency with increased serum levels of immunoglobulins M (HIGM1, MIM: #308230) [35], a laboratory finding of unknown significance commonly encountered in PBC [32]. In summary, we suggest that a progressively acquired haploinsufficiency for specific X-linked genes in peripheral lymphocytes may be a common mechanism for immunosenescence, the well-known state of dysregulated immune function that contributes to the increased susceptibility of the elderly to infection and, possibly, to autoimmune disease and cancer [36]. Our hypothesis may constitute the link across different peculiar characteristics of PBC, such as the genetic susceptibility, the role of microorganisms though molecular mimicry, and, most importantly, the female predominance.
Take-home messages .
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Primary biliary cirrhosis (PBC), similar to other autoimmune diseases, presents a high female to male ratio (estimated 9:1). No definitive explanation for the female predominance in autoimmunity has been found. Women with PBC manifest an enhanced rate of monosomy X in peripheral blood cells, compared with women with chronic hepatitis C infection or healthy women. The monosomy rates appear to increase with age in all groups and is not influenced by the severity of liver disease or the degree of cholestasis. Two possible models can be hypothesized. In the first, haploinsufficiency of specific X-chromosome genes involved in the mantainance of immune tolerance and escaping X inactivation is the key event. In the second, namely a multigenic complex inheritance model, the Y chromosome exerts a protective effect on susceptibility to PBC.
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References [1] Mackay IR, Whittingham S, Fida S, Myers M, Ikuno N, Gershwin ME, et al. The peculiar autoimmunity of primary biliary cirrhosis. Immunol Rev 2000;174:226 – 37. [2] Mackay IR, Van de Water J, Gershwin ME. Autoimmunity. Thoughts for the millennium. Clin Rev Allergy Immunol 2000;18:87 – 117. [3] Tanaka A, Borchers AT, Ishibashi H, Ansari AA, Keen CL, Gershwin ME. Genetic and familial considerations of primary biliary cirrhosis. Am J Gastroenterol 2001;96:8 – 15. [4] Selmi C, Mayo MJ, Bach N, Ishibashi H, Invernizzi P, Gish RG, et al. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology 2004 [in press]. [5] Talwalkar JA, Lindor KD. Primary biliary cirrhosis. Lancet 2003;362:53 – 61. [6] Selmi C, Gershwin ME. Bacteria and human autoimmunity: the case of primary biliary cirrhosis. Curr Opin Rheumatol 2004 [in press]. [7] Long SA, Van de Water J, Gershwin ME. Antimitochondrial antibodies in primary biliary cirrhosis: the role of xenobiotics. Autoimmun Rev 2002;1:37 – 42. [8] Lucey MR, Neuberger JM, Williams R. Primary biliary cirrhosis in men. Gut 1986;27:1373 – 6. [9] Floreani A, Paternoster D, Mega A, Farinati F, Plebani M, Baldo V, et al. Sex hormone profile and endometrial cancer risk in primary biliary cirrhosis: a case-control study. Eur J Obstet Gynecol Reprod Biol 2002;103:154 – 7. [10] Parikh-Patel A, Gold E, Utts J, Gershwin ME. The association between gravidity and primary biliary cirrhosis. Ann Epidemiol 2002;12:264 – 72. [11] Gartler SM, Goldman MA. Biology of the X chromosome. Curr Opin Pediatr 2001;13:340 – 5. [12] Sharp A, Robinson D, Jacobs P. Age-and tissue-specific variation of X chromosome inactivation ratios in normal women. Hum Genet 2000;107:343 – 9. [13] Kast RE. Predominance of autoimmune and rheumatic diseases in females. J Rheumatol 1977;4:288 – 92. [14] Chitnis S, Monteiro J, Glass D, Apatoff B, Salmon J, Concannon P, et al. The role of X-chromosome inactivation in female predisposition to autoimmunity. Arthritis Res 2000;2: 399 – 406. [15] Ranke MB, Saenger P. Turner’s syndrome. Lancet 2001;358: 309 – 14. [16] Davis CJ, Davison RM, Payne NN, Rodeck CH, Conway GS. Female sex preponderance for idiopathic familial premature ovarian failure suggests an X chromosome defect: opinion. Hum Reprod 2000;15:2418 – 22. [17] Valiaho J, Riikonen P, Vihinen M. Novel immunodeficiency data servers. Immunol Rev 2000;178:177 – 85. [18] Zinn AR. The X chromosome and the ovary. J Soc Gynecol Investig 2001;8:S34 – 6. [19] Invernizzi P, Miozzo M, Battezzati PM, Bianchi I, Grati FR, Simoni G, et al. Frequency of monosomy X in women with primary biliary cirrhosis. Lancet 2004;363:533 – 5.
[20] Guttenbach M, Koschorz B, Bernthaler U, Grimm T, Schmid M. Sex chromosome loss and aging: in situ hybridization studies on human interphase nuclei. Am J Hum Genet 1995;57:1143 – 50. [21] Kita H, Mackay IR, Van De Water J, Gershwin ME. The lymphoid liver: considerations on pathways to autoimmune injury. Gastroenterology 2001;120:1485 – 501. [22] Catalan J, Autio K, Kuosma E, Norppa H. Age-dependent inclusion of sex chromosomes in lymphocyte micronuclei of man. Am J Hum Genet 1998;63:1464 – 72. [23] Li R, Yerganian G, Duesberg P, Kraemer A, Willer A, Rausch C, et al. Aneuploidy correlated 100% with chemical transformation of Chinese hamster cells. Proc Natl Acad Sci U S A 1997;94:14506 – 11. [24] Carrel L, Cottle AA, Goglin KC, Willard HF. A first-generation X-inactivation profile of the human X chromosome. Proc Natl Acad Sci U S A 1999;96:14440 – 4. [25] Cazzola M, May A, Bergamaschi G, Cerani P, Rosti V, Bishop DF. Familial-skewed X-chromosome inactivation as a predisposing factor for late-onset X-linked sideroblastic anemia in carrier females. Blood 2000;96:4363 – 5. [26] Whitney AR, Diehn M, Popper SJ, Alizadeh AA, Boldrick JC, Relman DA, et al. Individuality and variation in gene expression patterns in human blood. Proc Natl Acad Sci U S A 2003;100:1896 – 901. [27] Carrel L, Willard HF. Heterogeneous gene expression from the inactive X chromosome: an X-linked gene that escapes X inactivation in some human cell lines but is inactivated in others. Proc Natl Acad Sci U S A 1999;96:7364 – 9. [28] Houldsworth J, Attardi G. Two distinct genes for ADP/ATP translocase are expressed at the mRNA level in adult human liver. Proc Natl Acad Sci U S A 1988;85:377 – 81. [29] Vogt MH, Goulmy E, Kloosterboer FM, Blokland E, de Paus RA, Willemze R, et al. UTY gene codes for an HLA-B60restricted human male-specific minor histocompatibility antigen involved in stem cell graft rejection: characterization of the critical polymorphic amino acid residues for T-cell recognition. Blood 2000;96:3126 – 32. [30] Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001;27:20 – 1. [31] Dahl HH, Hansen LL, Brown RM, Danks DM, Rogers JG, Brown GK. X-linked pyruvate dehydrogenase E1 alpha subunit deficiency in heterozygous females: variable manifestation of the same mutation. J Inherit Metab Dis 1992; 15:835 – 47. [32] Gershwin ME, Ansari AA, Mackay IR, Nakanuma Y, Nishio A, Rowley MJ, et al. Primary biliary cirrhosis: an orchestrated immune response against epithelial cells. Immunol Rev 2000;174:210 – 25. [33] Royer-Pokora B, Kunkel LM, Monaco AP, Goff SC, Newburger PE, Baehner RL, et al. Cloning the gene for an inherited human disorder-chronic granulomatous disease-on the basis of its chromosomal location. Nature 1986;322:32 – 8. [34] Gaya DR, Thorburn D, Oien KA, Morris AJ, Stanley AJ.
C. Selmi et al. / Autoimmunity Reviews 3 (2004) 493–499 Hepatic granulomas: a 10-year single centre experience. J Clin Pathol 2003;56:850 – 3. [35] Levy J, Espanol-Boren T, Thomas C, Fischer A, Tovo P, Bordigoni P, et al. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr 1997;131:47 – 54.
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[36] Castle SC. Clinical relevance of age-related immune dysfunction. Clin Infect Dis 2000;31:578 – 85. [37] Selmi C, Invernizzi P, Keefe EB, Coppel RL, Podda M, Rossaro L, et al. Epidemiology and pathogenesis of primary biliary cirrhosis. J Clin Gastroenterol 2004;38:264 – 71.
The World of Autoimmunity; Literature Synopsis Tumor necrosis factor alpha blocking and rheumatoid nodules The effect of infliximab (a tumor necrosis factor-alpha blocker) on the immunopathology of rheumatoid nodules was studied by Baeten et al. (Ann Rheum Dis 2004;63:489). They found no manifest immunopathological difference between the nodules before and after infliximab treatment, as all nodules had the classical structure with a central necrotic zone surrounding the palisade layer, and an outer connective tissue zone. Therefore, despite the improvement in articular symptoms associated with infliximab treatment, this therapy had no effect on the histopathology of rheumatoid nodules, suggesting that different mechanisms mediate these 2 disease manifestations in rheumatoid arthritis.
Thyroid autoimmunity in primary Sjogren’s syndrome There are several reports regarding an association between Sjogren’s syndrome and autoimmune thyroiditis. Tunc et al. (Ann Rheum Dis 2004;63:575) accordingly conducted a case-control study studying possible cooccurence of autoimmune thyroiditis in Sjogren’s syndrome. The overall frequencies of thyroid autoantibodies (anti-thyroglobulin and anti-thyroid peroxidase) was not significantly difference in a comparison between primary and secondary Sjogren’s syndrome and healthy controls. Only 2 patients having primary Sjogren’s sysndrome had clinical hypothyroidism associated with autoimmune thyroiditis.
Iga anti-annexin 5 autoantibodies in recurrent pregnancy loss The presence of IgG anti-annexin-A5 autoantibodies is an independent risk factor for unexplained fetal loss. They are also found in greater incidence in women with in vitro fertilization embryo transfer failures. Arai et al. (Am J Reprod Immunol 2003;50:202) tested whether IgA anti-annexin-A5 autoantibodies have similar associations. In search of these autoantibodies in 238 patients with early recurrent spontaneous abortion, 48 patients with recurrent in vitro fertilization embryo transfer failure, 179 non-pregnant women and 120 pregnant controls no difference was found between groups regarding IgA anti-annexin-A5 antibodies. The prevalence of these autoantibodies was also not different between patients with and without anti-phospholipid antibodies. Those patients having IgA anti-annexin-A5 autoantibodies bound annexin-A5 when it was free but not when it was associated with phospholipids. The results support no asssociation between IgA anti-annexin-A5 antibodies and reproductive failure.
Primary biliary cirrhosis: does X mark the spot? Carlo Selmi a,b,1, Pietro Invernizzi b,1, Monica Miozzo c, Mauro Podda b, M. Eric Gershwin a,* a
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, TB 192 One Shields Ave., Davis, CA 95616, USA b Division of Internal Medicine, San Paolo School of Medicine, University of Milan, Milan, Italy c Department of Medicine, Surgery and Dentistry, Laboratory of Human Genetics, San Paolo School of Medicine, University of Milan, Milan, Italy Received 17 March 2004; accepted 20 May 2004 Available online 25 June 2004
Abstract Primary biliary cirrhosis (PBC) is an autoimmune disease of unknown etiology leading to progressive destruction of intrahepatic bile duct, with cholestasis, cirrhosis, and eventually liver failure. Epidemiological data indicate that environmental factors trigger autoimmunity in genetically susceptible individuals, although no definitive association of PBC with specific genes has been found. Further, no convincing explanation has been provided for the strong female predominance observed in the prevalence of PBC. However, we recently suggested that the enhanced monosomy X in peripheral white blood cells, and particularly in lymphocytes, of affected women might play a role in the induction of PBC. Such observations appear independent from the degree of cholestasis and specific for PBC. In this review we discuss the implications of these findings and their immunological implications. D 2004 Published by Elsevier B.V. Keywords: Primary biliary cirrhosis; Female precominance; Monosomy X
Contents
1. Introduction . . . . . . . . . . . . . . . . . 2. Female predominance in PBC . . . . . . . . 3. The X Chromosome and the immune system 4. Monosomy X in PBC . . . . . . . . . . . . 5. Possible scenarios and concluding remarks . Take – home messages . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .
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* Corresponding author. Tel.: +1-530-752-2884; fax: +1-530-752-4669. E-mail address: [email protected] (M.E. Gershwin). 1 These authors equally contributed to this work. 1568-9972/$ - see front matter D 2004 Published by Elsevier B.V. doi:10.1016/j.autrev.2004.05.003
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494 494 494 495 497 497 498
494
C. Selmi et al. / Autoimmunity Reviews 3 (2004) 493–499
1. Introduction
Table 2 Sex ratios in PBC [37]
Primary biliary cirrhosis (PBC) has been an enigmatic disorder and unusual from the genetic perspective of the major histocompatibility complex (MHC) compared to other human autoimmune diseases [1]. Although the etiopathogenesis of human autoimmunity remains somehow enigmatic, we note that the majority of other immune mediated diseases have associations with genes or gene complexes within the major histocompatibility complex (MHC) [2]. In the case of PBC, such associations have been far less convincing [3]. However, the concordance of PBC between monozygotic twins [4] is higher when compared to other autoimmune diseases (Table 1). Nonetheless, PBC shares a number of features with other autoimmune diseases, including the presence of high titer autoantibodies against intracytoplasmic antigens, cell mediated responses against the same antigens, chronic inflammation, and a female predominance [5]. This latter observation has not been explained although a role for estrogens has been proposed. These features have led to the proposition that autoimmunity in PBC is produced by an environmental trigger, i.e. infection [6] or chemical xenobiotics [7], in a genetically predisposed individual [3]. Herein we present recent data on a role of specific X chromosome defects in
Year
Location
N of cases
M/F ratio
1983 1984 1984 1985 1990 1990 1995 1995 1997 2000
Newcastle, UK Malmoe, Sweden Western Europe Orebro, Sweden Ontario, Canada Northern England Victoria, Australia Estonia Newcastle, UK Olmsted county, MN (USA)
117 33 569 18 225 347 84 69 160 46
1:14 1:3 1:10 1:3.5 1:13 1:9 1:11 1:22 1:10 1:8
Table 1 Pairwise concordance rates of autoimmune disease in monozygotic and dizygotic twins (n of concordant sets/n of studied sets) (modified from Ref. [4])
Primary biliary cirrhosis Primary sclerosing cholangitis Systemic lupus erythematous Sjo¨gren’s syndrome Type I diabetes mellitus Rheumatoid arthritis Graves’ disease Multiple sclerosis Celiac disease
Monozygotic twins concordance rate
Dizygotic twins concordance rate
0.63 Concordant pair reported 0.24
0.00
Concordant pair reported 0.21 – 0.70a 12.3 – 15.4 0.17 – 0.29 0.25 – 0.31a 0.75 – 0.83
– 0.02
the induction of PBC and discuss the immunological implications.
2. Female predominance in PBC As observed for most autoimmune diseases, affected women, especially those of middle age, outnumber men by as much as 10:1 among PBC cases, although such ratio varies widely in different epidemiological studies (Table 2). Previous evidence once suggested that the natural history of PBC differs in males and females, with early onset asymptomatic PBC more common among men, accompanied by symptoms often not as severe as those seen in women. These data, however, have not been confirmed [8]. Sex hormones and their effects on the immune system have been often suggested as responsible for the female predominance in PBC. Nonetheless, data on sex hormones levels and metabolism in PBC have shown that the observed changes might be secondary to long-standing cholestasis [9]. One case-control study evaluated differences in reproductive history between women with PBC and matched controls using standardized questions and PBC cases had significantly more pregnancies than controls [10].
–
3. The X chromosome and the immune system 0.00 – 0.13 3.5 – 3.6 0.00 – 0.02 0.03 – 4.7 0.11
a Concordance rate following a minimum of 7.5 years of observation.
The biology of the X chromosome is unique, as there are two X chromosomes in females and only one copy in male individuals [11]. In mammals, X chromosome inactivation is the process that transcriptionally silences one of the two X chromosomes in
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females to compensate for the double dosage of Xlinked genes compared to males. In this process, maternal or paternal X chromosomes are randomly and independently inactivated in each cell, with an approximate 1:1 final ratio [12]. It has been postulated that females with autoimmunity may be particularly prone to a mechanism of ‘‘inadequate tolerization’’ by virtue of extremely skewed X chromosome inactivation [13]. In particular, an extreme skewing towards a single parental X chromosome may result in a situation in which polymorphic self-antigens on one X chromosome may fail to be expressed at sufficiently high levels in a tolerizing compartment, such as thymus, and yet may be expressed at a considerable frequency in the peripheral soma. Thus, women may be predisposed to a situation in which they can occasionally express X-linked autoantigens in the periphery to which they have been insufficiently tolerized. However, significant evidence has been raised discrediting this hypothesis [14]. A considerable number of sex- and immune-related genes have been mapped to the X chromosome; such genes appear crucial in the maintenance of physiological sex hormone levels and, more importantly, of immune tolerance, respectively. Monosomy or structural abnormalities of the X chromosome are present in genetic disorders such as Turner’s syndrome [15] or premature ovarian failure [16], often presenting accompanying autoimmune features. Moreover, we note that mutations in specific Xchromosome genes cause immunodeficiency syndromes characterized by different degrees of severity [17]. Finally, various X chromosome disorders can also be accompanied by signs of chronic cholestasis [15]. For these reasons, we hypothesized that X chromosome defects may play a role in the female preponderance of autoimmune diseases through alterations in the immune response.
4. Monosomy X in PBC X chromosomes may be an important determinant for the increased prevalence of PBC in women. While it cannot be excluded that sex hormones play a regulatory role in the natural history of PBC, the high number of sex- and reproduction-related genes on the
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human X chromosome [18] points towards defects of the X chromosome as more likely determinants for the altered sex ratio in the susceptibility to PBC. We have recently investigated the frequency of X chromosome monosomy in peripheral blood cells of 100 women with PBC and 100 age-matched women using fluorescent in situ hybridization [19]. We reported an enhanced monosomy X, that is a major defect of the X chromosome, in the peripheral blood cells of women with PBC, compared to controls. We also found that in PBC T and B lymphocytes presented this abnormality more frequently than other white blood cells. As previous reports indicated an age-dependent loss of the X chromosome in healthy adults [20], we also investigated monosomy X rates in 2 age-matched control groups composed of 50 healthy women and 50 women with chronic hepatitis C. The latter control group was also matched to patients with PBC for severity of disease. Finally, monosomy X was similar in PBC patients with and without cholestasis. Our results confirmed previously observed monosomy X rates in both control groups, thus ruling out a confounding effect of both age, altered liver function and cholestasis per se. Based on these data, we therefore suggested that a progressively acquired haploinsufficiency for specific X-linked genes may be involved in the etiopathogenesis of PBC, possibly through an instability of the X chromosome. Interestingly, the fact that monosomy X is more common in T and B cells than in other peripheral white blood cell subpopulations, suggests an explanation for the altered adaptive immune response demonstrated in PBC [21]. Although the molecular mechanisms are largely unknown, a progressive alteration of centromere function due to either faulty kinetochore proteins or premature centromere division can be hypothesized [22]. Alternatively, an accelerated aging process of involved cells may also be involved, likely due to the accumulation of subsequent errors in control mechanisms. As white cells in general and lymphocytes in particular are among the most mitotically active tissues of the body, they may also contain an increased frequency of such mitotic errors. Moreover, the rate of monosomic peripheral lymphocytes may indicate a larger cell population with micro-defects of the X chromosome, eventually associated with phenotypical changes. We also note that exposure to chemical and physical genotoxins can lead to loss of sex chromo-
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somes in peripheral blood cells [23]; such observations appear interesting in light of recent data suggesting a major role for chemicals (i.e. xenobiotics) in the onset of PBC [7]. Finally, we cannot rule out the possibility that the enhanced monosomy X may result from inheritance, as indirectly suggested by the strong genetic component encountered in PBC susceptibility [4]. The striking gender bias in incidence of PBC, together with the occurrence of X monosomy, prompted us to put forward a few hypotheses on the role that X-linked gene defects could play in PBC susceptibility. The search for X-linked candidate genes must consider that X chromosome in females is subjected to inactivation, to resolve X chromosome dosage between genders. The previously described mechanism of dosage compensation makes the genetically inherited monosomy X compatible with life, although with typical stigmata of Turner’s syndrome [15]. The impact of monosomy X on Turner’s syndrome phenotype has been attributed to the dosage deficiency of genes on the X chromosome which are normally expressed from both copies and are supplemented by functionally equivalent Y-linked homologous genes in male subjects [15]. A similar mechanism appears responsible for other female complex genetic disorders characterized by absence or by structural abnormality of the X chromosome [16]. Interestingly, a large number (up to 30%) of the X-linked genes have been recently shown to escape inactivation [24]. This appears interesting as the higher escape rate observed on the X chromosome may lead to increased frequency of disorders related to haploinsufficiency of specific genes. However, it is to note that although most of the X-linked genes escaping inactivation retain Y homologues and are located at PAR regions (Fig. 1), escape from silencing involves also genes outside PARs and not showing Y homologues. Because also males can develop PBC, in case of genes with homologue on Y chromosome, affected males have to display Y chromosome loss resulting in halfdosage of the putative genes. Alternatively, by considering genes escaping inactivation without evidence of a Y chromosome copy of the gene, i.e. EIF2S3, Y chromosome loss in affected males has not to be expected. In the future, it will be important to investigate whether sex chromosomes instability is present also in male patients with PBC, that is whether an Y
Fig. 1. Schematic G-banded representation of the human sex chromosomes. PAR1 and PAR2 (pseudoautosomal regions) indicate the main regions of homology between the sex chromosomes. On the left, genes discussed in the text as candidates for PBC development are shown (*indicates genes escaping X inactivation).
chromosome loss is more frequent in PBC male than in the healthy population. It seems interesting to note that, similarly to what described for X chromosome, an age-dependent loss of the Y chromosome has also been reported in healthy men [22]. It can also be hypothesized that the preferential loss of one of the two X chromosomes might unmask X-linked recessive mutations or polymorphisms. In this case, we have to presume that monosomy X preferentially involve one of the two X chromosome homologues. In addition, we have to presume that specific Y-linked genes exert a protective effect on X males. Indeed, being males constitutively hemizygous for the polymorphism, they would be more prone to PBC development than females. Futher, female carriers of certain X-linked immunodeficiencies provide hints to clarify the causes and implications of our findings. A progressive age-dependent nonrandom X inactivation [12] has been supposed to lead to the expression of recessive traits [25]. Similarly, it is possible that the clinical manifes-
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tations (or phenotype) of PBC might correlate with the amount of peripheral lymphocytes presenting insufficient expression of specific X-linked genes. Finally, the scenario is even more complex as recent studies point to individuality and variation in gene expression pattern in blood, mostly due to gender [26]. In addition, it has been reported that X-inactivation profile varies among female population [27]. Accordingly, future studies aimed to investigate genetic profile of candidate genes in PBC population must take into account also the peculiarity of X-linked genes expression profile in female population.
5. Possible scenarios and concluding remarks Based on our findings, we hypothesize two possible genetic models providing a connection between PBC and the candidate genes that future molecular studies of X chromosome abnormalities may identify. First, a polygenic model with an Xlinked major locus of susceptibility is suggested, with genes escaping X chromosome inactivation as the major candidates. Possible candidate genes include ANT3, escaping inactivation and also active on Y homologue, coding for the ADP/ATP mitochondrial carrier of liver [28], and several genes of the H – Y minor histocompatibility antigen [29]. Second, we hypothesize a multigenic complex inheritance model in which Y chromosome genes might exert a protective role, in case of preferential X chromosome loss or of skewed X inactivation that unmask X-linked recessive mutations or polymorphisms. A possible candidate gene could be JM2/FOXP3, involved in the pathogenesis of the X-linked-allergic dysregulation syndrome and the syndrome of immunodysregulation, polyendocrinopathy, and enteropathy (XLAAD, MIM: 304790) [30]. Similarly, the pyruvate dehydrogenase E1-alpha gene (PDHA1) [31] should also be considered. Interestingly, PDHA1 is one of the enzymatic components of pyruvate dehydrogenase complex family, the wellknown autoantigens of PBC-specific AMA [32]. Other genes mapping on the X chromosome, such as GP91-PHOX gene, also appear interesting. Mutations of GP91-PHOX, in fact, cause the X-linked chronic granulomatous disease (CGD, MIM:
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#306400), characterized by recurrent bacterial and fungal infections, as well as formation of granulomas [33]. Intriguingly, liver epithelioid granulomas are found in up to 80% of patients with PBC, but seldom in other hepatobiliary diseases, with the exception of sarcoidosis and tubercolosis [34]. Finally, the CD40 ligand (CD40L) gene is known to induce, through mutations, an X-linked immunodeficiency with increased serum levels of immunoglobulins M (HIGM1, MIM: #308230) [35], a laboratory finding of unknown significance commonly encountered in PBC [32]. In summary, we suggest that a progressively acquired haploinsufficiency for specific X-linked genes in peripheral lymphocytes may be a common mechanism for immunosenescence, the well-known state of dysregulated immune function that contributes to the increased susceptibility of the elderly to infection and, possibly, to autoimmune disease and cancer [36]. Our hypothesis may constitute the link across different peculiar characteristics of PBC, such as the genetic susceptibility, the role of microorganisms though molecular mimicry, and, most importantly, the female predominance.
Take-home messages .
. .
.
Primary biliary cirrhosis (PBC), similar to other autoimmune diseases, presents a high female to male ratio (estimated 9:1). No definitive explanation for the female predominance in autoimmunity has been found. Women with PBC manifest an enhanced rate of monosomy X in peripheral blood cells, compared with women with chronic hepatitis C infection or healthy women. The monosomy rates appear to increase with age in all groups and is not influenced by the severity of liver disease or the degree of cholestasis. Two possible models can be hypothesized. In the first, haploinsufficiency of specific X-chromosome genes involved in the mantainance of immune tolerance and escaping X inactivation is the key event. In the second, namely a multigenic complex inheritance model, the Y chromosome exerts a protective effect on susceptibility to PBC.
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The World of Autoimmunity; Literature Synopsis Tumor necrosis factor alpha blocking and rheumatoid nodules The effect of infliximab (a tumor necrosis factor-alpha blocker) on the immunopathology of rheumatoid nodules was studied by Baeten et al. (Ann Rheum Dis 2004;63:489). They found no manifest immunopathological difference between the nodules before and after infliximab treatment, as all nodules had the classical structure with a central necrotic zone surrounding the palisade layer, and an outer connective tissue zone. Therefore, despite the improvement in articular symptoms associated with infliximab treatment, this therapy had no effect on the histopathology of rheumatoid nodules, suggesting that different mechanisms mediate these 2 disease manifestations in rheumatoid arthritis.
Thyroid autoimmunity in primary Sjogren’s syndrome There are several reports regarding an association between Sjogren’s syndrome and autoimmune thyroiditis. Tunc et al. (Ann Rheum Dis 2004;63:575) accordingly conducted a case-control study studying possible cooccurence of autoimmune thyroiditis in Sjogren’s syndrome. The overall frequencies of thyroid autoantibodies (anti-thyroglobulin and anti-thyroid peroxidase) was not significantly difference in a comparison between primary and secondary Sjogren’s syndrome and healthy controls. Only 2 patients having primary Sjogren’s sysndrome had clinical hypothyroidism associated with autoimmune thyroiditis.
Iga anti-annexin 5 autoantibodies in recurrent pregnancy loss The presence of IgG anti-annexin-A5 autoantibodies is an independent risk factor for unexplained fetal loss. They are also found in greater incidence in women with in vitro fertilization embryo transfer failures. Arai et al. (Am J Reprod Immunol 2003;50:202) tested whether IgA anti-annexin-A5 autoantibodies have similar associations. In search of these autoantibodies in 238 patients with early recurrent spontaneous abortion, 48 patients with recurrent in vitro fertilization embryo transfer failure, 179 non-pregnant women and 120 pregnant controls no difference was found between groups regarding IgA anti-annexin-A5 antibodies. The prevalence of these autoantibodies was also not different between patients with and without anti-phospholipid antibodies. Those patients having IgA anti-annexin-A5 autoantibodies bound annexin-A5 when it was free but not when it was associated with phospholipids. The results support no asssociation between IgA anti-annexin-A5 antibodies and reproductive failure.