Is There An Immunogenetic Basis for Peyronie's Disease?

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VOI 157. 295-297. January 1997 Prinfed i n U . S . A

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IS THERE AN IMMUNOGENETIC BASIS FOR PEYRONIE’S DISEASE? MARY S. LEFFELL From th(, D e p r t i n e n t

Medicine, orid Deparlrnerit of Molcwilar Microbiology and Immunology, School of Hygiene and Public H
of Medicine, School of

ABSTRACT

Purpose: Despite numerous studies, there has been no definitive HLA association with Peyronie’s disease. Results of available studies have been reviewed and compared to determine if t h e cumulative evidence supports any immunogenetic, HLA association with Peyronie’s disease. Materials and Methods: D a t a from reports of HLA associations with Peyronie’s disease were reanalyzed by categories of reported HLA class I o r class I1 antigens i n comparison with recently available large population analysis of t h e frequencies of these antigens in the normal population. D a t a were also considered by whether they were derived from population or family analyses. Results: T h e results of 4 series of patients testing an association of Peyronie’s disease with the HLA class I antigens, i n particular t h e B7 related antigens, were contradictory. A B7 association was not confirmed in 2 larger series and, i n fact, t h e B7 related antigens were observed i n frequencies expected i n a normal population, suggesting that the associations observed i n t h e smaller series were due to chance. An association with t h e HLA class I1 antigen, DQ2, was found i n 1of t h e larger series. Reported family studies suggest a genetic basis for Peyronie’s disease but do not indicate a gene closely linked to the HLA complex. Conclusions: Considering all available data, Peyronie’s disease appears to be multifactorial in pathogenesis. Because Peyronie’s disease is likely heterogeneous and because available studies have analyzed serologically defined HLA antigens, future studies to define HLA alleles molecularly a n d to characterize patient subgroups may clarify a n immunogenetic basis. KEY WORDS:penile induration, HLA antigens, disease susceptibility, autoimmune diseases POSSIBLE MECHANISMS FOR MAJOR HISTOCOMPATIBILITY Although the etiology of Peyronie’s disease remains obCOMPLEX (HLA) DISEASE ASSOCIATIONS scure, it has been suggested that there may be an immunoThere are several hypothetical mechanisms to explain the genetic basis. One hypothesis is that mechanical stress or other factors may trigger an inherent fibroplastic and possi- association between HLA antigens and various diseases, inbly autoimmune response.1.2 Somers et a1 demonstrated that cluding Peyronie’s disease. Four general explanations are cell cultures derived from Peyronie’s plaques have an en- currently considered plausible based on knowledge of the hanced fibroproliferative capacity.3 It is possible that an au- molecular structure and function of the major histocompatitoimmune response triggers or potentiates cell proliferation bility complex gene products.15-17 Disease associations that culminates in a fibrotic plaque characterized by exces- may be related to the role of class I (HLA-A, B, C) and class sive amounts of collagen. The histopathology of Peyronie’s I1 (HLA-DR, DQ, DP) histocompatibility molecules in preplaques is consistent with this theory, since early lesions senting peptide antigens to T lymphocytes, since antigen are characterized by inflammatory infiltrates. As the dis- presentation is vital to the induction of normal immune reease progresses the plaques become more fibrotic and in sponses and to the establishment of self-tolerance. In particular, some class I1 alleles appear to predispose to the develsome cases calcified.4-6 An underlying autoimmune patho- opment of certain autoimmune disorders, including insulingenesis has also been suggested by the coincidence of dependent diabetes, rheumatoid arthritis and others.15 Peyronie’s disease with other fibroplastic disorders, includAs a second hypothesis, defects in other nonhistocompatibiling Dupuytren’s contracture, plantar fibromatosis and ity genes, such as the C2, C4 and Bf complement components, knuckle pads. Diabetes, a recognized autoimmune disorder, could af€ect immune regulation. Other nonhistocompatibility may also be coincident.7.s More recent evidence supporting candidates for predisposing major histocompatibility complex the involvement of autoimmune factors in Peyronie’s disease genes are the recently defined TAP and LMP genes that are is the demonstration of increased serum levels of anti-elastin involved in antigen antibodies in Peyronie’s disease patients.9 The third hypothesis, or the theory of “molecular mimicry,” The first evidence suggestive of an immunogenetic basis proposes that microbial pathogens may share epitopes with came from studies of the association of Peyronie’s disease some major histocompatibility complex molecules.’6 Due to with certain HLA antigens, specifically HIA-B27 and closely their immunological similarity or cross-reactivity, these related members of the B7 cross-reactive g r o ~ p . l O -HOW~~ pathogens may escape immune destruction andor provoke ever, the association of B7 cross-reactive group antigens with an autoimmune response. As a final possibility, an HLA may simply be due to linkage of a disease causing Peyronie’s disease has not been confirmed in larger s e r i e ~ . ~ . ’association ~ More recently, Rompel et a1 reported associations with the gene to the major histocompatibility complex, such as the HLA class I1 antigens, DR3 and DQ2, reopening the possi- case for hemachromatosis and 2 1-hydroxylase deficieney.17 bility of an immunogenetic basis for Peyronie’s d i s e a ~ e . ~ . ~ Based on reported associations, the 2 hypotheses most

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IMMUNOGENETICS OF PEYRONIE’S DISEASE

likely relevant to Peyronie’s disease are molecular mimicry and the possession of an HLA allele that is somehow permissive for the development of Peyronie’s disease through antigen presentation. Molecular mimicry has been suggested to have a role in the pathogenesis of the B27 associated spondyloarthropathies, including ankylosing spondylitis, Reiter’s syndrome and reactive arthritis. This suggestion has been drawn from studies identifylng cross-reactivity or mimicry between the HLA-B27 molecule and various gram-negative bacteria, including Salmonella, Shigella, Yersinia and Klebsiella. l4-22 Serologic cross-reactivity has been clearly shown with binding studies using monoclonal antibodies, although patient antibody responses and/or cellular reactivity to the putative pathogens or shared epitopes has yielded conflicting results.21.22 If an HLA-B27 association could be established, molecular mimicry could be a plausible factor in Peyronie’s disease. The suggestion is attractive because localized fibrotic lesions, similar to fibrotic Peyronie’s plaques, sometimes occur in the B27 associated spondyloarthropathies. Aside from the B27 associated spondyloarthropathies, the overwhelming majority of diseases with established HLA associations are clearly autoimmune in nature and are most strongly associated with class I1 HLA, DR or DQ antigens. In this regard, the reports of an association of Peyronie’s disease with the HLA class I1 antigens, DR and DQ2, are intriguing and suggest a possible underlying immunological pathogenesis related to the role of the class I1 molecules in antigen pre~entation.~.8 RESULTS OF UNRELATED PATIENT SERIES

The first report of an HLA association with Peyronie’s disease was in 1979 by Willscher et al.10 In their series of 8 cases of idiopathic disease only 2 were positive for HLA B27 but when the antigens of the B7 cross-reactive group were considered collectively, a significant association was obtained. For reference, the currently recognized antigens of the B7 cross-reactive group are listed in table 1 along with the antigen frequencies in normal white subjects. It should be noted that the B7 antigens are not uncommon among white subjects, with a total expected frequency of greater than 50%. Deguchi et al reported no significant association of the B7 cross-reactive group antigens in a series of 9 Japanese patients with Peyronie’s disease.” However, they only considered B7 and B27 in their analysis, each of which was obReexamination of their data, served with frequencies of 11%. including all of the currently recognized B7 antigens, revealed additional patients with related antigens, including B54, B60 and B61, with an overall frequency of 78%. This incidence compares with a frequency of 53.9% in the normal Japanese population.23 These reported associations of B7 cross-reactive group antigens in Peyronie’s patients have not been confirmed in 2 larger series by Rompe17v8 and Leffell14 et al. A combined

TABLE 1. Frequencies of the HLA-B7 cross-reactiue group antigens in white subjects Antieen*

46 Freouencvt

BI 822 (854.55.56) B27 B40 (60.61)

25.3 5.0 8.1 13.3 1.5 0.4

B41

B47 B48 Total

0.3 ~

53.9 * Splits of primary or broad antigen specificity are indicated in parentheses. t Phenotype frequencies were obtained from analysis of 8,789 white organ donors from the Renal Regiatry of the United Network for Organ

summary of data from these 2 studies is given in table 2. The frequencies of the B7 cross-reactive group antigens among the patients are compared to the respective frequencies in normal white subjects. The individual antigen frequencies in both studies approximate those of the normal population. Moreover, the combined B7 cross-reactive group frequencies in both series are slightly lower than the total B7 crossreactive group frequency in the normal population. Based on these observations, it seems likely that the associations noted in earlier studies can be attributed to chance due to small sample sizes. To date, the only reported association of any class I1 antigen with Peyronie’s disease has been by Rompel et a1.i H They observed deviations from the expected normal antigen frequencies of HLA-DR3 and DQ2, with the association of DQ2 being highly significant (corrected P value <0.005). Interestingly, they also noted slight increases in the frequencies of the class I antigens A1 and B8. As noted by these authors, HLA-A1; B8; DR3; DQ2 is a common haplotype in white subjects, and one that has been associated with numerous autoimmune disorders. In particular, this haplotype is increased in patients with insulin-dependent diabetes.15 which raises the possibility of the HLA association seen with Peyronie’s disease resulting from the coincidence of diabetes. ANALYSIS OF FAMILIAL TRANSMISSION

While analyses of unrelated patient series have not estahlished a n HLA association, family studies have indicated genetic transmission and supported an association with the B7 cross-reactive group antigens. Ziegelbaum et a1 reported the occurrence of B27 in identical twins with Peyronie’s disease.12 A mare extended study by Nyberg et al included 3 multi-generation families. l3 In addition to Peyronie’s disease in the kindreds, they also found a 78% coincidence of Dupuytren’s contracture, a figure substantially greater than in previous reports. In 1family there was father-to-son transmission of Peyronie’s disease and Dupuytren’s contracture in 3 generations. Pedigree analysis suggested that Peyronic.’s disease is an autosomal dominant trait but, while B7 crossreactive group antigens occurred in all 3 families, inheritance of Peyronie’s disease was clearly independent of the H I h gene complex. The authors concluded that there is a major autosomal dominant gene but that Peyronie’s disease is likely polygenic, with certain HLA alleles serving as “intcracting or modifying factors.”’3 CONCLUSIONS

Although familial transmission indicates a genetic basis for Peyronie’s disease, the collective data do not support a strong HLA association. However, there are several issues that should be considered before any definite conclusions concerning a n immunogenetic basis for this disorder can he reached. Peyronie’s disease appears to be multifactorial, and as noted by Ziegelbaum et a1 disease expression may require the genetic component and an environmental trigger.” Potential environmental factors should be analyzed, perhaps starting with the microbes suggested to be molecular mimics of HLA-B27 and its closely related B7 cross-reactive group antigens. TABLE 2. Frequency of B7 cross-reactiue group antigens i n Peyronie’s disease oatients

HLAAntigen B7 B22 B27

B40 Totals

~

~

~

et (52 pts.)’

Controls $ (8,789 ‘pts. li ’

25.0

23.1

3.6

.?R _ -

25.3 5.0

3.6 10.7 42.9

7.7 9.6 44.2

8.1 13.3 51.7

__

IMMUNOGENETICS OF PEYRONIE’S DISEASE

297

creased serum levels of anti-elastin antibodies in patients with Peyronie’s disease may also be heterogeneous. For examPeyronie’s disease. J. Urol., 162 105, 1994. ple, the disease in patients with another coincident disease, such as Dupuytren’s contracture, may be different in etiology 10. Willscher, M. K , Cwazka, W. F. and Novicki, D. E.: The association of histocompatibility antigens of the B7 cross-reacting and expression than cases of isolated Peyronie’s disease. group with Peyronie’s disease. J. Urol., 122 34, 1979. Similarly, patients with diabetes and Peyronie’s disease may T., Maeda, S., Sakai, S., Kuriyama, M., Kawada,Y. and represent a different entity than those with coincident 11. Deguchi, Nishiura, T.: HLA-A and B antigens in patients with Dupuytren’s contracture. It is possible in some disease subPeyronie’s disease. Urology, 23 547, 1984. groups that HLA alleles may display an epistatic effect. 12. Ziegelbaum, M., Thomas, A., Jr. and Zachary, A. A: The associAdditional studies will be required to address these issues ation of Peyronie’s disease with HLA B7 cross-reactive antibut the most productive approaches seem clear. Patient gens. A case report of identical twins. Cleve. Clin. J. Med., 64: groups should be carefully characterized for other coincident 427, 1987. disorders. These subgroups must then be analyzed for any 13. Nyberg, L. M., Jr., Bias, W. B., Hochberg, M. C. and Walsh, P. C.: Identification of a n inherited form of Peyronie’s disease differences in disease expression and genetic factors. Addiwith autosomal dominant inheritance and association with tional typing for HLA class I1 antigens is warranted but the Dupuytren’s contracture and histocompatibility B7 crosscoincidence of any known autoimmune disorders must be reacting antigens. J. Urol., 1%. 48, 1982. considered. To date, the studies of HLA association with 14. Leffell, M. S., Devine, C. J., Jr., Horton, C. E., Somers, K. D., Peyronie’s disease have been performed using serological Dawson, D. M., Vande Berg, J. S., Bluemink, G. G. and typing methods that do not define HLA subtypes or alleles. Wright, G. L., Jr.: Non-association of Peyronie’s disease with Future analysis of HLA associations should be performed by HLA B7 cross-reactive antigens. J. Urol., 127: 1223, 1982. molecular methods, since it is becoming evident that disease 15. Nepom, G. T.: MHC class-I1 molecules and autoimmunity. Ann. subsets may be associated with HLA alleles that differ only Rev. Immunol., 9: 493, 1991. in particular nucleotide sequences. (For example, in rheuma- 16. Tiwari, J. L. and Terasaki, P. I.: HLA and Disease Associations. New York Springer-Verlag, 1985. toid arthritis it has been clearly shown that more severe forms of disease are associated with certain subtypes or al- 17. Thomas, G.: HLA disease associations: models for insulin dependent diabetes mellitus and the study of complex human geleles of HLA-DR4.24) If there are different clinical subsets of netic disorders. Ann. Rev. Genet., 2 2 31, 1988. Peyronie’s disease and if HLA can be a factor in pathogene18. Bodmer, J. G., Marsh, S. G., Albert, D. E., Bodmer, W. F., sis, then different allelic associations should become apparDupont, B., Erlich, H. A,, Mach, B., Mayr, W. R., Parham, P., ent. Sasazuki, T., Schreuder, G. M. T., Strominger, J. L., Svejgaard, A. and Terasaki, P. I.: Nomenclature for factors of REFERENCES

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