BACKGROUND/AIMS:Recent studies have suggested that the course of chronic hepatitis C may be influenced by the immunogenetic background of the host. Specifically, HLA-DR11 (5) has been associated with less advanced hepatitis C virus (HCV)-related liver disease. The aim of the present study was to investigate whether HLA-DRB1*11 subtypes or HLA-DQA1 and DQB1 genes might be associated with protection from or susceptibility to chronic HCV infection, histological severity of HCV-induced liver disease and infecting HCV genotype.METHODS:Ninety-nine unrelated outpatients with histologically documented chronic hepatitis C were studied and their allele frequencies were compared with those of 179 ethnically matched controls and with those of 41 HCV RNA-positive patients with persistently normal aminotransferase levels (HCV carriers). HLA-DQ types and HLA-DRB1*11 subtypes were determined by polymerase chain reaction gene amplification with sequence specific primers.RESULTS:None of 10 DQA1 or 12 DQB1 alleles was significantly associated with susceptibility to or protection from chronic HCV infection or with histological staging or with HCV genotype. However, analysis of DQA1-DQB1 combinations showed that DQA1*0201-DQB1*0201 combination was significantly more frequent in patients compared to controls, both in cis (26.3% vs 16.2%, p = 0.04, odds ratio = 1.8, 95% confidence interval, 0.96-3.5) and in trans (12.1% vs. 1.1%, p = 0.0001, OR = 12.2, 95% CI, 2.6-113.7). HCV carriers did not differ from controls or from patients in the frequency of DQA1-DQB1 combinations. The extended haplotype DRB1*1104, DQA1*0501, DQB1*0301 was seen significantly less frequently in patients than in controls (8% vs 22.3%, p = 0.0025, OR = 0.31, 95% CI, 0.12-0.7) or HCV-RNA carriers (8% vs 26.8%, p = 0.003, OR = 0.24, 95% CI, 0.08-0.73).CONCLUSIONS:Immunogenetic factors may play a role in determining both protection from and susceptibility to chronic hepatitis C, the trans-dimer DQA1*0201-DQB1*0201 predisposing to and the DRB1*1104, DQA1*0501, DQB1*0301 haplotype protecting from chronic hepatitis C.

There is evidence that hepatitis C virus (HCV) may be vertically transmitted from infected mothers to their children, although it is uncertain to what extent maternal transmission occurs.1 Major maternal risk factors include the HIV-HCV coinfection and a high HCV-RNA titer at delivery; moreover viral subtypes 1b and 3a seem to be most frequently transmitted.2, 3 To evaluate the influence of fetal genetic factors on the acquisition of infection, we examined the polymorphisms of the major histocompatibility complex in 24 mother-infant pairs. We studied 24 children born to HCV-infected mothers, 7 of whom had vertically HCV-infected (PCR for HCV positive and active antibodies to the virus after 12 months of follow-up at least) infants and 17 reverted from seropositivity to seronegativity between 9 and 12 months of age. HLA-DRB1* low resolution genomic typing was performed by PCR-reverse dot-blot whereas PCR-sequence-specific primers was applied for DRB1*, DRB3*, DRB4*, DRB5* high resolution and for DQA1* and DQB1* definition. The most striking difference in HLA gene frequencies of HCV-positive children compared with those of seroreverters was in the HLA-DRB1* 1101 and 1104 genes. The HLA-DRB1*1101 allele was significantly associated with longstanding HCV positivity [21.42% in HCV-positive children vs. 2.9% in HCV-negative children; chi square, 4.44; P = 0.035; odds ratio (OR), 9.00]; conversely the HLA DRB1* 1104 seemed to be related with resistance to infection (0% in HCV-positive vs. 20.5% in HCV-negative; chi square, not significant; P not significant; OR, not determined). No difference was found in the HLA-DQA1 and DQB1 allele distribution. Because the only difference between these two DRB1* 11 subtypes (1101, 1104) is in the glycine/valine dimorphism at position 86 of the antigen-binding site which plays a pivotal role in allorecognition,4 we studied the DRβ86V and DRβ86G frequencies in the HCV-positive children and in the seroreverters. The DRB1*Gly86 frequency was significantly higher in the persistently infected subjects (85.7% vs. 52.9%; chi square, 4.54; P = 0.033; OR = 5.33), whereas valine appeared more frequently in the seroreverters (47.05% vs. 14.3%; chi square, 4.54; P = 0.033; OR = 0.19). We also noticed that the DRβ86VV homozygous genotype was present only in the seroreverters (23.5% vs. 0% in the HCV-positive children); on the contrary the frequency of DRβ86GG appeared increased in the HCV-infected children (71.4% vs. 29.4%) (Table 1).TABLE 1It appears that DRβ86 has a critical role in fetal susceptibility or resistance to maternal HCV infection. We suggest that valine in DRβ86 alters the conformation of the peptidebinding cleft so that it does not permit the arrangement of a steady complex with the viral peptides and results in a low risk of HCV infection. In support of the hypothesis that DRβ86V correlates with infant protection from viral infection, it has been recently observed that in infants born to HIV-infected mothers, DRB1*1501 and DRB1* 1301 alleles (both Val86) were significantly associated with seroreversion status.5 Although our results must be considered preliminary, they could form a useful starting point for more detailed investigations regarding the genetic susceptibility to virus C infection in infants born to infected mothers. Miryam Martinetti, B.S. Ilaria Pacati, M.D. Cristina Daielli, B.S. Laura Salvaneschi, M.D. Anna Maccabruni, M.D. HLA Laboratory; Department of Transfusion Medicine (MM, CD, LS); Institute of Infectious Diseases (IP, AM); University of Pavia; IRCCS Policlinico S. Matteo; Pavia, Italy

The combined use of surnames, which simulate selectively neutral genetic markers, and HLA genes may constitute a useful tool for the genetic survey of a small area. We found a coincidence between HLA genetic structure and surname ‘selectively neutral’ pattern, in an Italian province, although HLA genes indicate a more pronounced genetic isolation for one particular subregion of the province. The patchiness of HLA allele distribution that is sometimes created by drift and/or selection can be used as the basis both of anthropological and of epidemiological studies. The creation of genetic maps of relatively small areas may also constitute a tool for the selection of bone marrow donors.

HLA class I (HLA-A, HLA-B) and class II (HLA-DR, HLA-DQ) gene frequencies in 6 subareas of Pavia province are calculated in two samples of bone marrow donors. We estimated the degree of genetic differentiation between the 6 sub-areas through the standardized variance FST. On the basis of the island migration model the number of migrants is estimated from FST and compared with the observed migration index in the province according to the 1991 census.

Tissue AntigensVolume 47, Issue 4 p. 341-343 A novel Italian haplotype predominates in HLA-B45-positive bone marrow donors: HLA-A2, CW*1601, B45, DRB1*1101, DRB3*0301, DQA1*0102, DQB1*0502 C. Daielli, C. Daielli Laboratorio HLA, Servizio di Immunoematologia e Trasfusione, IRCCS Policlinico S. Matteo, PaviaSearch for more papers by this authorL. Salvaneschi, L. Salvaneschi Laboratorio HLA, Servizio di Immunoematologia e Trasfusione, IRCCS Policlinico S. Matteo, PaviaSearch for more papers by this authorG. Ghidini, G. Ghidini Centro Trasfusionale e di Immunologia, Presidio Ospedaliero Cremonese, Cremona, ItalySearch for more papers by this authorF. Ambroselli, F. Ambroselli Laboratorio HLA, Servizio di Immunoematologia e Trasfusione, IRCCS Policlinico S. Matteo, PaviaSearch for more papers by this authorC. Gatti, C. Gatti Laboratorio HLA, Servizio di Immunoematologia e Trasfusione, IRCCS Policlinico S. Matteo, PaviaSearch for more papers by this authorM. Martinetti, Corresponding Author M. Martinetti Laboratorio HLA, Servizio di Immunoematologia e Trasfusione, IRCCS Policlinico S. Matteo, PaviaLaboratorio HLA Servizio di Immunoematologia e Trasfusione IRCCS Policlinico S. Matteo Piazzale Golgi, 2 1–27100 Pavia Italy Fax +39–382-527965Search for more papers by this author C. Daielli, C. Daielli Laboratorio HLA, Servizio di Immunoematologia e Trasfusione, IRCCS Policlinico S. Matteo, PaviaSearch for more papers by this authorL. Salvaneschi, L. Salvaneschi Laboratorio HLA, Servizio di Immunoematologia e Trasfusione, IRCCS Policlinico S. Matteo, PaviaSearch for more papers by this authorG. Ghidini, G. Ghidini Centro Trasfusionale e di Immunologia, Presidio Ospedaliero Cremonese, Cremona, ItalySearch for more papers by this authorF. Ambroselli, F. Ambroselli Laboratorio HLA, Servizio di Immunoematologia e Trasfusione, IRCCS Policlinico S. Matteo, PaviaSearch for more papers by this authorC. Gatti, C. Gatti Laboratorio HLA, Servizio di Immunoematologia e Trasfusione, IRCCS Policlinico S. Matteo, PaviaSearch for more papers by this authorM. Martinetti, Corresponding Author M. Martinetti Laboratorio HLA, Servizio di Immunoematologia e Trasfusione, IRCCS Policlinico S. Matteo, PaviaLaboratorio HLA Servizio di Immunoematologia e Trasfusione IRCCS Policlinico S. Matteo Piazzale Golgi, 2 1–27100 Pavia Italy Fax +39–382-527965Search for more papers by this author First published: April 1996 https://doi.org/10.1111/j.1399-0039.1996.tb02564.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Terasaki PI. Microdropet assay for human blood lymphotoxins. In: Histocompatibility testing Washington, DC: National Academy of Sciences, 1965: 17. 2 Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988: 16: 1215. 3 Olerup O, Zetterquist H. HLA-DR typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours: an alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation. Tissue Antigens 1992: 39: 225–35. 4 Bignon JD, Fernandez-Vina M. PCR-SSO protocol for the HLA-DNA typing technique. In: D Charron, R Fauchet, ed. Twelfth International Histocompatibility Workshop and Conference. Technical handbook Paris: HLA et Médicine, 1994: 1–27. 5 Piazza A, Olivetti E, Griffo RM et al. The distribution of HLA antigens in Italy. Gene Geography 1989: 3: 141–64. 6 Imanishi T, Akaza T, Kimura A, Tokunaga K, Gojobori T. Allele and haplotype frequencies for HLA and complement loci in various ethnic groups. In: K Tsuji, M Aizawa, T Sasazuki, ed. HLA 1991: Proceedings of the XI International Histocompatibility Workshop and Conference. Vol. 1. Oxford: Oxford Science Publications, 1992: 1065–1220. 7 Moses JH, Sadler AM, Heyes JM et al. HLA class I SSP ARMS-PCR typing kit. In: Twelfth International Histocompatibility Workshop and Conference. Reference manual London: Tissue Antigen Laboratory, Imperial Cancer Research Fund, 1994: 6–12. 8 Yang SY, Milford E, Hammerling U, Dupont B. Description of the reference panel of B-lymphoblastoid cell lines for factors of the HLA system: the B-cell line panel designed for the tenth International Histocompatibility Workshop. In: B Dupont, ed. Histocompatibility testing 1987. New York: Springer-Verlag, 1987: 9–11. Volume47, Issue4April 1996Pages 341-343 ReferencesRelatedInformation

Bone marrow transplantation (BMT) from unrelated volunteers is frequently associated with both increased incidence and increased severity of acute graft-versus-host disease (GVHD). In the last years, it has been suggested that the analysis of the frequency of cytotoxic T lymphocyte precursors (CTLp) of unrelated HLA-matched donors can be used to detect disparity for HLA class I antigens and as a predictive test for development of severe GVHD. In this report, we summarized our experience regarding 20 pediatric patients affected by various hematological disorders, receiving allogeneic BMT from unrelated donors, HLA class I and II antigens of donor/recipient pairs were determined by means of serological typing, whereas molecular typing of HLA-class II antigens of patients and their potential donors was performed using PCR-SSP and PCR-fingerprinting techniques. CTLp values, estimated using limiting dilution analysis, were high (range, 1:7000-1:40,000) in 9 of 20 patients, while the other 11 children had low or undetectable levels (<1:100,000) of CTL precursors. CTLp frequency was compared with the incidence and severity of GVHD observed after BMT. Our data demonstrate that the frequency of donor CTLp does not statistically correlate either with the occurrence of clinically significant acute GVHD or with disparity for HLA-class II molecular typing between donor and recipient. In particular, 4 of the 10 evaluable patients with an undetectable CTLp frequency developed grade IV, III, II, and IV acute GVHD, respectively. Although the limited number of subjects studied does not allow us to draw any firm conclusion, our data suggest a certain caution in considering this test suitable for the selection of potential donors.

HLA study was performed in 9 absolute non-responder (serum titre of anti-HBsAg < 2 mIU ml-1) and 8 hyporesponder (serum antibody level between 2 and 9.9 mIU ml-1) babies who underwent, in neonatal period, HBV vaccination with Engerix B recombinant vaccine. The investigation pointed out that many of these subjects carry HLA haplotypes classically involved in autoimmune diseases: namely HLADR7; DQ2, DR4; DQ8 and DR3; DQ2. The genomic typing for DRB1, DRB3, DRB4, DRB5, DQA1, DQB1 and DPB1 genes revealed an increased frequency of the DRB1*0701; DQA1*0201; DQB1*0201 haplotype (23.5 vs 9.9% of the controls) and of DPB*0201 allele (42.3 vs 13.2% of controls). The polymorphism of Bf, C4A and C4B complement serum components, recognized as important "immune-function-related genes", pointed out an increased frequency of the null allele C4AQ0 (34.3 vs 6.8% of the controls) stressing the role of C4A serum complement component in response to foreign peptide. The immunogenetic investigation has been extended to 23 responder babies (titre of anti-HBsAg > 50 mIU ml-1), vaccinated with the same trial as the poor responders. The HLA frequencies observed in this group were comparable to those of control population and, with respect to the HLA markers cited above, absolutely different from the non/hyporesponder infants. From the HLA class II sequence analysis in the group of poor-responder babies some characteristics, peculiar to autoimmune diseases, have been observed: the majority of the infants showed at least an arginine at the 52 residue of the alpha chain of DQ molecule and a non-aspartic acid at the 57 position of the DQ beta chain.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied the HLA polymorphisms (class I, II, and III) in 107 Italian patients with biopsy specimen-proven sarcoidosis in order to investigate the immunogenetic background of this disease. The mean age of onset of the disease was 36.08 +/- 12.4 years. Four patients (3.73 percent) were in radiologic stage 0, 38 patients (35.51 percent) were in radiologic stage 1, 40 patients (37.38 percent) were in stage 11, and 25 (23.36 percent) were in stage III. Thirty-eight patients (35.51 percent) had one or more extrapulmonary localization(s) of the disease. Positive association between sarcoidosis and HLA-B8 (chi2 = 6.07, p = 0.0127, RR = 1.91) was confirmed. Regarding the age of onset of the disease, HLA-B35 was more frequent (chi2 = 7.34, p = 0.0056, pc <0.05, RR = 4.62) i'' patients with early onset of symptoms and/or signs, before the mean age of 36 years. With reference to the radiologic stage of the disease, HLA class II marker DR3 was more frequent in patients with stage I (chi2 = 7.22, p = 0.0061, pc < 0.05, RR = 7.08). No significant relationship was found between sarcoidosis and HLA class III markers. These results seem to confirm an association of sarcoidosis with HLA classic genes and can sustain the hypothesis of a genetic heterogeneity of this disease.

Ninety-four cryptorchids, 50 monolateral and 44 bilateral, aged from 2-9.4 yr (mean, 5.1 +/- 0.5 yr), were studied for the hormonal and immunogenetic profile. Pituitary-gonadal function was studied by evaluation of basal and peak GnRH-stimulated serum FSH and LH. In 83 cases, the serum testosterone (T) level was measured before and after CG treatment. No significant differences, between patients and age-matched controls, were found in either FSH or LH levels, whether under basal conditions or after GHRH stimulation. The mean basal serum T level was similar in mono and bilateral cryptorchids and in controls but, on the 15th day after treatment, it was significantly lower in the bilateral cryptorchids (P less than 0.05). CG administration led to testicular descent in 42 patients (23 with monolateral and 19 with bilateral cryptorchidism) and failed in 41 (21 with monolateral and 20 with bilateral cryptorchidism), independently of T increase. Immunogenetic investigation demonstrated that HLA-A11 and A23 were significantly overrepresented in the whole group of cryptorchids in comparison with the controls (P = 0.004 and P = 0.0123, respectively). HLA-A11 was more common in the bilateral form (P less than 0.05), whereas HLA-A29 was more frequent in the monolateral one (P less than 0.05). Forty percent of the bilateral cryptorchids with unsuccessful treatment had the HLA-A11 allele (P less than 0.01) and 70% the HLA-DR5.