Psychological factors in the prognosis of malignant melanoma: a prospective study.

Sixty-four patients with Stage I or II malignant melanoma who were apparently disease free rated the amount of adjustment needed to cope with their illness on a scale of 1 to 100. The resultant figure was called the melanoma adjustment score. Twenty-nine patients who relapsed within 1 year of surgery reported a score of 53 +/- 31 (mean +/- SD); 35 nonrelapsers reported a score of 80 +/- 20, p less than 0.001. Based upon analysis of indivual melanoma adjustment scores in the first 31 patients, we predicted that subjects scoring greater or equal to 65 would stay in remission, whereas those scoring greater than 65 would relapse. Applying this prospectively to the next 33 patients we correctly identified 25 of 33 outcomes (76%), p less than 0.03. This psychological variable was independent of known biological prognostic factors, which did not predict 1 year survival. The melanoma adjustment score was also independent of the number of positive lymph nodes, which did correlate with outcome in these patients. The results suggest a role for psychological factors in the one year prognosis of this malignancy.

Gluten-sensitive enteropathy: genetic analysis and organ culture study in 35 families.

The genetic marker histocompatibility antigen HLA-B8 is present in 80% of patients with gluten-sensitive enteropathy (GSE). We studied 35 families with at least one affected member to determine whether an HLA-region gene alone could determine susceptibility to GSE. The incidence of HLA-B8 in the patients was 69% vs 22% for normals (P less than 0.001). The incidence of GSE in HLA-genotype-identical siblings of patients was only 8%, and in HLA-B8-haplotype-identical siblings and parents of patients was only 14% and 5%, respectively. In addition, intestinal biopsies of HLA-identical or partially identical relatives of patients were studied in an in vitro organ culture system capable of detecting gluten sensitivity in subjects ingesting a normal diet. The results confirmed the low incidence of gluten sensitivity in these individuals. The organ culture system could not differentiate mucosa obtained from unaffected parents or siblings of patients with GSE (who presumably carry the HLA-associated genetic information) from mucosa obtained from normals. We conclude that the genetic material inherited with HLA-B8 alone is not sufficient to produce clinical or subclinical disease. Other genetic and environmental factors appear to be important for disease pathogenesis.

Increase in titer of the naturally occurring human antibody to neuraminidase-treated lymphocytes after influenza.

Nine of 25 (36%) humans suffering from naturally acquired influenza A infection developed significant increases in the titer of a "naturally" occurring antibody to neuraminidase-treated human lymphocytes. Only two of 43 normal and noninfluenza respiratory infection controls showed titer changes of this antibody, p less than 0.001. The antibody was not directed at influenza virus C fixation, hemagglutination inhibition, or neuraminidase antigens. Three of 10 normals given a highly immunogenic, formalin-killed influenza A vaccine developed significant titer rises. These results suggest that influenza virus, live or dead, can provoke an increase in antibody to a cross-reacting antigen present on neuraminidase-treated human lymphocytes.

Immunogenetic analysis and serum viral antibody titers in multiple sclerosis.

In order to investigate the possible relationships between multiple sclerosis (MS) and the factors of genetic predisposition and exposure to infectious agents, studies were undertaken in 59 male patients with MS to determine the histocompatibility antigen (HL-A) type and the serum antibody titer to rubeola hemagglutinin (HA), rubeola envelope antigen (V), rubeola nucleocapsid antigen (S), rubella, herpes simplex, cytomegalovirus, and parainfluenza 1. The incidence of HL-A7 was significantly higher, and HL-A12 incidence was significantly lower, in the MS group than in control groups. The geometric mean titers to rubeola HA and to the V and S antigens were lower in the HL-A7 positive control patients than in either the non-HL-A7 controls or the MS patients. There were no specific relationships of the rubeola titer to HL-A12. Antibody titers to the other viruses studied were not significantly different in MS patients as compared to controls, nor was there any relationship of HL-A7 or HL-A12 and serum titer to those viruses. This study provides further evidence of a genetic predisposition to MS, and of a relationship between rubeola and this disease. These findings suggests that the failure of MS to appear in individuals who might be genetically predisposed to this disorder may be related to their immune response to rubeola.

Host factors and antibody response Haemophilus influenza type b meningitis and epiglottitis.

Levels of antibody in serum after infection with Haemophilus influenza type b or challenge with polysaccharide vaccine are highly variable. Convalescent-phase serum antibody to the capsular polysaccharide of H. influenzae type b was measured in two groups of patients with pathophysiologically distinct diseases, meningitis and acute epiglottitis. Antibody response after H. influenzae meningitis was subnormal. Mean levels of antibody, the distribution of antibody levels by age, and erythrocyte and genetic marker lymphocyte antigens were studied; all results suggested that these two groups of patients were genetically and immunologically different from each other. Evidence suggested that the magnitude of the important host immunologic response was under host genetic control.

Rhesus lymphocyte alloantigens. III. Identification of new antigens.

Rhesus monkey lymphocytotoxic alloantisera were tested in 437 random unrelated monkeys and in members of 19 pedigreed families. Groups of sera or individual sera identified 11 specificities. Genetic analysis of the associations of these antigens revealed behavior consistent with the current concept of the major histocompatibility complex of several mammalian species including man in that the antigens could be grouped into two series of closely linked co-dominantly expressed alleles.

Progress in rhesus histocompatibility typing resulting from the Second International Nonhuman Primate Histocompatibility Workshop (1973).

The Second International Nonhuman Primate Histocompatibility Workshop permitted comparison of rhesus monkey alloantisera developed in various laboratories on a single common panel of related and unrelated monkeys. Analysis of the data permits the conclusion that at least nine specificities are recognized by more than one laboratory, including six at the first locus and three at the second locus.

The pathogenesis of gluten-sensitive enteropathy.

Gluten-sensitive enteropathy is characterized by flattening of intestinal villi and malabsorption caused by the toxic effect of gluten, a wheat protein. Gluten activates an endogenous mechanism of toxicity that may be the local mucosal immune system: local mucosal immunoglobulin and antigluten antibody production occur soon after gluten ingestion. Approximately 80% of patients with this disease possess HL-A8, a second segregant series antigen. This association also occurs in dermatitis herpetiformis, a disease with vesicular skin lesions and gluten-sensitive flattening of intestinal villi. The association suggests that the fundamental abnormality in enteropathy is a binding reaction involving gluten protein and a binding site on a cell surface, determined in part by the histocompatibility gene; this reaction then results in a local mucosal immune response to gluten. Alternatively, the fundamental abnormality may be the presence of an abnormal immune-response gene linked to the HL-A8 gene or acting in concert with it; this immune-response gene results in local mucosal production of antigluten antibody.

Anti-HL-A7 lymphocyte-dependent antibody.

Target cell specificity of a human cytotoxic lymphocyte-dependent antiserum correlated with the presence of HL-A7 on target cells. Target cells from 10 of 11 HL-A7-positive donors were damaged in vitro by this antiserum together with lymphocytes from normal donors. Target cells from six donors lacking HL-A7 were not damaged. Cytotoxic activity was removed by adsorption of the antiserum with lymphocytes from any one of four HL-A7-positive donors. Adsorption with lymphocytes from any one of three HL-A7-negative donors failed to eliminate cytotoxic activity.

Prolonged survival in bronchogenic carcinoma associated with HL-A antigens W-19 and HL-A5: a preliminary report.

The HL-A antigens were determined retrospectively in a group of 14 surgically cured bronchogenic carcinoma patients and prospectively in another group of 100 untreated patients. In the retrospective group, the frequencies of antigens W-19 and HL-A5 were significantly increased when compared with the noncancer control and the prospective lung cancer populations. In the latter group, 60% of the patients with W-19 and 58% with HL-A5 survived without evidence of tumor for at least 1 year after treatment compared with 15% of patients with neither of these antigens, P less than 0.01 and 0.005, respectively. These comparisons were for adenocarcinoma and squamous carcinoma. The patient groups for oat cell and undifferentiated carcinoma were too small for valid statistical comparisons. This preliminary study suggests that the presence of HL-A antigens W-19 and HL-A5 confers resistance to dissemination of bronchogenic carcinoma.

Histocompatibility antigens and solid malignant neoplasms.

To evaluate the relation between histocompatibility antigen phenotypes and solid malignant neoplasms, HL-A type was determined in 633 cancer patients and compared with those of 489 normal controls. HL-A8 was elevated in patients with squamous cancer, melanoma, and adenocarcinoma. The highest incidence occurred in patients with salivary gland adenocarcinoma (67% vs only 17% in normal controls). A threefold increase in HL-A5 was detected in patients with connective tissue sarcomas (28% incidence vs 9% in normal controls). Antigen frequencies did not vary when analyzed by time of diagnosis or interval after treatment. The finding that certain malignant neoplasms have associations with increased frequency of individual HL-A antigens may give clues to cause and genesis for these tumors.

Multiple primary malignant neoplasms. A search for an immunogenetic basis.

The occurrence of multiple primary malignant neoplasms in single individuals is well documented. Although many hypotheses have been advanced to explain this occurrence, there has been no study to determine if a presumed "increased susceptibility to cancer" has an immunogenetic basis. We evaluated the cellular immunity and histocompatibility antigens of 42 patients who had had from two to four multiple primary malignant neoplasms. We failed to demonstrate a preexisting impairment of immunocompetence or abnormal HL-A antigen frequencies in these patients. The occurrence of multiple primary malignant neoplasms in related tissues, eg, lung/larynx/oral cavity, and the occurrence of successive primary malignant neoplasms at a time interval consistent with the patient's being cured of preceding malignant neoplasms suggest that multiple primary malignant neoplasms result from repetitive induction by the same or similar etiologic factors in patients who are cured after treatment of the first malignant neoplasm.

Pathology of modified graft-versus-host disease in bone marrow allografted monkeys treated with antilymphocyte serum.

Lethally irradiated rhesus monkeys were used for bone marrow allografting and autografting. Monkeys receiving allogeneic bone marrow developed acute graft-versus-host reaction (GVHR) and had a mean survival time of 9.1 days as compared to autografted monkeys which survived above 500 days. Treatment with antilymphocyte sera (ALS) before allografting modified the GVHR and extended the survival time to an average of 43 days. Histologically, such animals showed evidence of "chronic" GVHR and septicemia secondary to a lack in lymphoreticular recovery. Subsequently, severe GI-tract infections followed which usually served as portal of entry for septicemia.

Dermatitis herpetiformis. Immunologic concomitants of small intestinal disease and relationship to histocompatibility antigen HL-A8.

In the present study the relation between the gluten-sensitive intestinal lesion observed in dermatitis herpetiformis (DH) and in gluten-sensitive enteropathy (coeliac sprue) (GSE) was analyzed. Jejunal IgA synthesis in DH was estimated from the extent of incorporation of [(14)C]leucine into IgA in jejunal biopsy specimens during short-term in vitro culture. Patients with DH have significantly elevated incorporation values as compared to normal control individuals (18,880+/-13,614 vs. 5,830+/-3,190 cpm/mg tissue protein/ 90 min) (P < 0.02) and the degree of elevation correlates well with the degree of morphologic abnormality. Thus patients with DH are similar to patients with GSE where elevated local mucosal IgA synthesis has also been observed. By using both morphologic and immunologic criteria for evaluating intestinal status, patients with DH and intestinal disease were distinguished from patients with DH free of intestinal disease. Of the eight patients in the former group, seven carried HL-A8 (87.5%), an incidence which is strikingly similar to that observed in patients with GSE alone (88.5%). In contrast, of the seven patients in the latter group (without gastro-intestinal disease) two had HL-A8, an incidence (27%) not significantly different from that in the normal population (20%) (P > 0.1).Thus, both in respect to local mucosal increase in IgA synthetic rates and in respect to the association with HL-A8, the intestinal lesion of DH is similar to that of GSE.