Relation between skin cancer and HLA antigens in renal-transplant recipients

BACKGROUND. Recipients of renal allografts are at an increased risk for skin cancer. It is also known that recipients who are homozygous for HLA antigens are at an increased risk for certain cancers, as are those who are mismatched with their donors for these antigens. In a case-control study we assessed the relation between skin cancer in renal-transplant recipients and HLA homozygosity and mismatching. METHODS. Of 764 patients who received renal transplants between 1966 and 1988, 66 had squamous-cell carcinoma or basal-cell carcinoma of the skin after transplantation. HLA homozygosity was assessed in all 66 recipients, and HLA mismatching in 39; the results were compared with those in 124 recipients without skin cancer. We also investigated the relation between skin cancer and the use of immunosuppressive drugs. In separate case-control analyses we investigated the influence of exposure to the sun and keratotic skin lesions on the risk of skin cancer. RESULTS. The risk of squamous-cell carcinoma was increased in recipients mismatched for HLA-B antigens; the relative risks were 2.6 (95 percent confidence interval, 1.1 to 6.5) and 5.0 (95 percent confidence interval, 1.3 to 19.0) with mismatching for one and two antigens, respectively, as compared with no mismatching. Mismatching for HLA-A or HLA-DR antigens had no effect on the risk of squamous-cell carcinoma, and there was no association between mismatches at any of the HLA loci and the occurrence of basal-cell carcinoma. The total doses of azathioprine and prednisone were not associated with the occurrence of skin cancer or with HLA matching. Exposure to sunlight and keratotic skin lesions were strongly associated with skin cancer but not with HLA mismatching. Homozygosity for HLA-DR was more frequent among the patients with squamous-cell carcinoma (relative risk, 2.5; 95 percent confidence interval, 0.95 to 4.6) and among patients with 100 or more keratotic skin lesions (relative risk, 4.8; 95 percent confidence interval, 1.5 to 15.1). CONCLUSIONS. HLA-B mismatching is significantly associated with the risk of squamous-cell carcinoma in renal-transplant recipients, as is HLA-DR homozygosity. An indirect effect on the level of immunosuppression does not appear to explain these findings, nor does exposure to sunlight or the number of keratotic skin lesions account for this observation.     

HLA serological cross-reactivity: HLA-B15 has two public antigens

On the basis of their serologic cross-activity, HLA antigens can be organized into cross-reactive groups of CREG's. We have recently defined immunochemically two public alloantigenic determinants X and Y which can account for the serological cross-reactivity of the B7-CREG and B5-CREG, respectively. One of the smaller of these CREG's consists of HLA-B15 and B17. Using microcytotoxicity testing, a fluoresceinated Protein A binding assay, and chemical immunoprecipitation techniques, we have defined a new public alloantigenic determinant, tentatively designated “Z,” which is present on the 44,000 dalton glycoprotein chains of HLA-B15 and HLA-B17, but distinct from the B15 and B17 determinants. Since HLA-B15 is also a member of the B5-CREG, and therefore bears allodeterminant Y, this report constitutes the first immunochemical demonstration of two public determinants. Y and Z, on a single HLA-B molecule, HLA-B15.     

Alloimmunization by blood group antigens from bone allografts

The purpose of this report is to heighten awareness of the risk of blood group antigen sensitization following hone allografting. Two Rh-negative females of childbearing age developed multiple antibodies to Rh antigens following transplantation of bone from Rh-positive donors. A previous pregnancy and/or blood transfusions were ruled out as factors influencing the antibody production. It is postulated that red cells or red cell stroma in the allografts stimulated the antibody production. Therefore, young, Rh-negative bone allograft recipients at risk (especially women) should receive Rh-negative bone allografts. Alternatively, they should receive Rh immune globulin at the time of transplanting if the allograft is from an Rh-positive donor. Bone allografts processed to deplete the hemopoietic marrow and red cells should minimize the risk of blood group antibody sensitization.     

Iron stores in multi-transfused thalassaemic patients seem not to be influenced by the HLA system

The HLA-A and -B antigens of 99 Greek patients with transfusion dependent homozygous beta thalassaemia were determined. The HLA antigen distribution in thalassaemic patients with a severe transfusion siderosis and in patients without signs of siderosis were compared to that of 400 healthy unrelated controls from the same population. There is an increase of HLA-B 14 antigen in both groups of thalassaemics as compared with the controls. No significant difference exists in the distribution of all the other HLA antigens between the two sub-groups of thalassaemics or with the controls.     

HLA antigens in psoriasis

In the group (N = 136) of psoriatic patients 27 HLA antigens determined by A and B loci were identified. Phenotype, gene and haplotype frequencies were calculated and compared with the control data. A significant association between psoriasis and HLA-B13 and/or HLA-B17 was confirmed. The relative risk for these antigens amounted to 2.3 and 4.4 respectively. Among all haplotypes calculated for the psoriatic population there were only six with significant relative risk ranging from 3.1 to 27.4. Unexpectedly, the highest relative risk (27.4) was found for haplotype HLA-A9, X.     

Utility of peritransplant and rescue intravenous immunoglobulin and extracorporeal immunoadsorption in lung transplant recipients sensitized to HLA antigens

The role of anti-human leukocyte antigen (HLA) antibodies in lung transplantation is not fully clear. The presence of pretransplant third-party anti-HLA antibodies or the development of de novo anti-HLA antibodies has been associated with acute posttransplant complications, bronchiolitis obliterans syndrome (BOS), and early mortality in some studies. However, little has been reported regarding the utility of desensitization therapy in sensitized lung transplant recipients. For approximately 3 years, desensitization therapy consisting of intravenous immunoglobulin (IVIG) and, in most instances, extracorporeal immunoadsorption (ECI) has been administered peritransplant to lung transplant recipients at our institution with third-party anti-HLA antibodies or as rescue therapy to those who develop de novo anti-HLA antibodies. Notably, the administration of peritransplant desensitization therapy to these patients has been associated with improvement in several clinical parameters, including acute rejection and BOS. Furthermore, administration of rescue IVIG with or without ECI has been associated with an overall improvement in the rate of pulmonary function decline. Our experience suggests that desensitization therapy may be beneficial for lung transplant recipients with pretransplant or de novo anti-HLA antibodies. We discuss the appropriateness and clinical impact of IVIG and ECI in sensitized lung transplant recipients as well as cellular mechanisms that may contribute.     

HLA antigens in brucellosis

106 patients diagnosed as having brucellosis were typed for HLA class I and class II antigens. The number of healthy controls was 272 and 102 for classes I and II, respectively. 17 HLA-A, 31 HLA-B, 7 HLA-C and 8 HLA-DR specificities were studied. The most important finding was a highly significant decrease of the HLA-Cw2 antigen frequency in the patient group compared with the controls. The corrected p value was p less than 0.0001 (Fisher's test). This finding is compatible with the idea that HLA-Cw2 antigen could be a protective factor. No other positive or negative association was observed. There was no significant difference in HLA antigen frequencies between patients with and without joint manifestations. In addition, we did not find an HLA-B27 increase in the group of patients with brucellosis associated spondylarthritis when compared with healthy individuals.     

HLA antigens in uveitis

HLA antigens are associated with a number of inflammatory eye diseases, most notably HLA B2 with anterior uveitis (AU). This association varies between different populations and ethnic groups. The aim of this study was to investigate the relationship between uveitis and HLA A, B and DR locus antigens in an Australian population. Seventy-two consecutive patients with uveitis were studied (37 males and 35 females) over a 6 month period. Thirty-two percent of the AU patients were HLA B27+, as were 42% of males (19% females) with their first attack of AU compared with 60% of males (23% females) with recurrent AU. The only significant difference in etiology between males and females was the greatly increased incidence of rheumatic diseases in males, in whom 77% (10/13) had radiological evidence of sacroiliitis. Additional findings included a lack of association between the HLA B7 cross reactive group and DR locus antigens in AU as well as the lack of any HLA associations in the 13 patients with posterior uveitis (PU).     

HLA antigens influence resistance to lung carcinoma

The concept of genetic factors playing a role in the pathogenesis of lung cancer has gained increased attention. The present study was undertaken to reexamine the question of HLA antigen association with carcinoma of the lung. In a study of 90 patients, a significant association occurred between HLA-DR7 and resistance to lung cancer, after accounting for smoking status and sex. HLA class I antigens were also implicated. These results suggest that major histocompatibility complex loci affect carcinoma of the lung.     

HLA antigens and susceptibility to myasthenia gravis

HLA-A, -B, -C and -DR antigen frequencies determined in a group of 73 myasthenia gravis (MG) patients were compared with those of a control group of 205 subjects. The strongest positive association with MG was found antigens B8 and DR3 (relative risks 9.56 and 8.84 respectively). Analysis of our data indicates that both antigens, independently from their linkage disequilibrium, are involved in susceptibility to MG. No relationship between HLA antigens on thymic pathology was observed in our material. In male MG patients the association with DR3 was weaker than in female patients. The difference in DR3 frequency between male and female patients was statistically significant; no significant difference was found for antigen B8. It appears that DR3 contributes to development of MG only in females. In male patients aged more than 30 years at the onset of disease, MG was not associated with B8 or DR3. In contrast, in female patients aged more than 30 years at the onset of disease there was a strong association of B8 and DR3 with the disease.     

HLA antigens in familial hyper-alphalipoproteinemia

Tissue typing for HLA-A, B and C antigens was performed in 28 subjects belonging to a family in which an inherited increase of high density lipoprotein cholesterol (HDL-C) is present. Nine subjects had definite hyper-alphalipoproteinemia (HDL-C greater than 80 mg/dl) and 3 "borderline" values (HDL-C greater than 70 mg/dl). There is not any linkage between the presence of HDL-C elevation and the HLA haplotypes.     

HLA antigens in pityriasis versicolor

The distribution of 30 HLA antigens was studied in 48 patients with Pityriasis Versicolor and 134 controls. No significant deviations were found in the patient group after correction for the number of antigens tested.     

HLA antigens in Hirschsprung''s disease

In 55 children with Hirschsprung's disease, 64 of their normal siblings and 120 other members of their families, HLA-A, B and C types were examined. The statistical significance of the raised incidence of A1, B14, B37 and Bw35 in the patients disappeared after correction for multiple testing. The levels of homozygosity were very similar in patients and normal controls. The results indicate no direct association of the disease with HLA type.     

HLA antigens in geographic tongue

HLA-A,B,C phenotyping was performed on 95 patients with geographic tongue to determine whether there is an increased frequency of any particular allele in this condition. An increased frequency of B15 was found in the patients when compared to normal controls. When the patients were divided into atopic and non-atopic groups there was an increased frequency of B15 and a decreased frequency of B40 in the atopic group compared to the controls. B40 was as decreased in the atopic group when compared to the non-atopic group. When the type I correction factor was applied to the probability values the differences in antigen frequencies in all cases became insignificant.     

HLA antigens in chronic pancreatitis

Since immunological and hereditary factors may be important in chronic pancreatitis, histocompatibility antigens of classes I and II were studied in 50 British Caucasian patients, after exclusion of insulin-dependent diabetics for whom HLA associations are recognised. Chronic pancreatitis was defined by at least two independent criteria, and only subjects with alcohol-related and idiopathic disease were included. In 22 patients (21 male), weekly ethanol intake had chronically exceeded 100 g (usually substantially so); the remaining 28 had idiopathic chronic pancreatitis (ICP). Twenty patients (40%) had autoantibodies, in 11 (22%) to gastric parietal cells. Nine of those with ICP (three male) had parietal cell antibody, more than expected for the age/sex distribution. There were overall increased frequencies of HLA Cw5 and B44. In ICP there were increased frequencies of HLA A25 and Cw1, and a decreased frequency of B7. In patients with alcohol-related disease there were increased frequencies of Cw5 (50.0% vs control 15.9%), B44 (54.5% vs 29.4%), and DR4 (61.1% vs 33.6%). The increased frequency of Cw5 in alcohol-related disease alone remained significant after correction (p less than 0.05). A hypothesis that hereditary and possibly immunological factors may contribute to the aetiology of chronic pancreatitis is supported.     

HLA antigens in sarcoidosis.

The HLA antigens were identified in sixty-five patients with sarcoidosis, comprising forty-five with uveitis, twelve with erythema nodosum and eight with arthritis. In the group with arthritis, B8 was present in seven of eight (P = 0-0016) and the haplotype 1,8 in five of eight (P = 0-0053). A1 was present in 44% with uveitis (P = 0-04). There was no other significant disturbance of antigen frequencies in uveitis or in erythema nodosum, but it was noteworthy that B27 was present in only two patients with uveitis.