Journal of the Neurological Sciences, 1977, 32:79-89
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© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
HLA P H E N O T Y P E A2 ;B12 IN V I T A M I N Blz N E U R O M Y E L O P A T H Y *
M. A. HORTON and R. T. D. OLIVER Department of Haematology and the ICRF Department of Medical Oncology, St. Bartholomew's Hospital and Medical College, London ECIA 7BE (Great Britain)
(Received 17 September, 1976)
SUMMARY Severe neurological complications (either peripheral neuropathy, subacute combined degeneration of the cord or cerebral changes) are a characteristic feature in some patients with marked vitamin B12 deficiency. Although Addisonian pernicious anaemia (PA) is the major cause of this neurological syndrome, the disorder has been described in association with other conditions in which there is a profound depletion of vitamin B12 stores. Sixteen patients with vitamin B12 neuromyelopathy, associated with PA, have been HLA-typed for 27 alleles of the A and B loci and compared with 53 cases of PA without neurological damage and 60 controls of the same ethnic group. There is a significantly increased frequency of the HLA phenotype, A2 ;B12 (44 ~ instead of 4 in PA patients without neurological damage) in the disease group studied (P < 0.0005). The significance of these findings in relation to the pathogenesis of vitamin B12 neuromyelopathy is discussed.
INTRODUCTION Recently certain antigens of the major histocompatibility system have been shown to be associated with human diseases (Svejgaard, Platz, Ryder, Staub-Nielsen and Thomsen 1975), many, but not all, of which appear to have an immune pathogenesis. Evidence from animal models indicates the existence of genes, lying within or near the chromosomal region of the major histocompatibility locus, which control disease susceptibility or resistance; it is possible that these genes are identical with * A preliminary communication was presented at the 1st International Symposium on HLA and Disease, Paris, 23-25 June, 1976. Financial support for this study was provided by the ICRF (RTDO) and Wellcome Trust (MAH).
80 those which are involved in the control of immune responsiveness (McDevitt and Bodmer 1974). Similar mechanisms might, in theory, explain the relationship between HLA and disease in man, although they still remain to be proven. Reports of studies of HLA antigen frequencies in Addisonian pernicious anaemia, a disease in which organ-specific autoimmune mechanisms are thought to play a role, have, with one exception (Eastmond and Woodrow 1976), shown a possible, though weak, association with the HLA antigen B7 (Mawhinney, Lawton, White and Irvine 1975; Whittingham, Youngchaiyud, Mackay, Buckley and Morris 1975; Zittoun, Zittoun, Seignalet and Dausset 1975; Horton and Oliver 1976), particularly after analysis of combined data (Svejgaard, A., personal communication). This antigen has previously only been shown to be associated with paralytic poliomyelitis and multiple sclerosis; we have previously drawn attention to the absence of any association between HLA-B7 and neurological disease coexisting within our group of PA patients (Horton and Oliver 1976). We have subsequently enlarged our study of A and B locus HLA antigen and phenotype frequencies in cases of PA with neurological complications, the results of which are reported below. METHODS Patients Sixteen patients (8 male and 8 female) with neurological damage associated with vitamin Blz deficiency were studied; this represents an incidence of neurological disease in association with PA of approximately 13 ~. The haematological findings in the patients are shown in Table 1. The cases were selected from a series of PA patients under investigation at St. Bartholomew's Hospital, in whom the haematological criteria for diagnosis were based upon the demonstration of vitamin B12 malabsorption corrected by intrinsic factor in the absence of gastric surgery or small intestinal disease, megaloblastic bone marrow changes, a low serum vitamin B12 level, a full response to vitamin B12 replacement and in the majority of cases, autoantibodies to gastric parietal cells or intrinsic factor. Only patients with evidence of peripheral neuropathy, posterior column or pyramidal tract involvement for which no other cause could be found and in whom a partial or complete reversal of signs occurred in response to vitamin B12 therapy alone, were HLA-typed; cases in which distal paraesthesiae or diminished ankle jerks were present as an isolated finding were not included in the study. The clinical and neurological features are summarised in Table 2. HLA typing HLA typing was performed using platelet complement fixation (Cotombani, Colombani, Dehay and Dausset 1970) and standard NIH lymphocytotoxicity sera defining 11 antigens of the A locus and 16 antigens of the B locus, as well as the complex specificities "4a" and "4b". Control groups for HLA antigen frequencies consisted of 53 patients suffering from PA without neurological disease and 60 healthy staff members of St. Bartholomew's Hospital.
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79
© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
HLA P H E N O T Y P E A2 ;B12 IN V I T A M I N Blz N E U R O M Y E L O P A T H Y *
M. A. HORTON and R. T. D. OLIVER Department of Haematology and the ICRF Department of Medical Oncology, St. Bartholomew's Hospital and Medical College, London ECIA 7BE (Great Britain)
(Received 17 September, 1976)
SUMMARY Severe neurological complications (either peripheral neuropathy, subacute combined degeneration of the cord or cerebral changes) are a characteristic feature in some patients with marked vitamin B12 deficiency. Although Addisonian pernicious anaemia (PA) is the major cause of this neurological syndrome, the disorder has been described in association with other conditions in which there is a profound depletion of vitamin B12 stores. Sixteen patients with vitamin B12 neuromyelopathy, associated with PA, have been HLA-typed for 27 alleles of the A and B loci and compared with 53 cases of PA without neurological damage and 60 controls of the same ethnic group. There is a significantly increased frequency of the HLA phenotype, A2 ;B12 (44 ~ instead of 4 in PA patients without neurological damage) in the disease group studied (P < 0.0005). The significance of these findings in relation to the pathogenesis of vitamin B12 neuromyelopathy is discussed.
INTRODUCTION Recently certain antigens of the major histocompatibility system have been shown to be associated with human diseases (Svejgaard, Platz, Ryder, Staub-Nielsen and Thomsen 1975), many, but not all, of which appear to have an immune pathogenesis. Evidence from animal models indicates the existence of genes, lying within or near the chromosomal region of the major histocompatibility locus, which control disease susceptibility or resistance; it is possible that these genes are identical with * A preliminary communication was presented at the 1st International Symposium on HLA and Disease, Paris, 23-25 June, 1976. Financial support for this study was provided by the ICRF (RTDO) and Wellcome Trust (MAH).
80 those which are involved in the control of immune responsiveness (McDevitt and Bodmer 1974). Similar mechanisms might, in theory, explain the relationship between HLA and disease in man, although they still remain to be proven. Reports of studies of HLA antigen frequencies in Addisonian pernicious anaemia, a disease in which organ-specific autoimmune mechanisms are thought to play a role, have, with one exception (Eastmond and Woodrow 1976), shown a possible, though weak, association with the HLA antigen B7 (Mawhinney, Lawton, White and Irvine 1975; Whittingham, Youngchaiyud, Mackay, Buckley and Morris 1975; Zittoun, Zittoun, Seignalet and Dausset 1975; Horton and Oliver 1976), particularly after analysis of combined data (Svejgaard, A., personal communication). This antigen has previously only been shown to be associated with paralytic poliomyelitis and multiple sclerosis; we have previously drawn attention to the absence of any association between HLA-B7 and neurological disease coexisting within our group of PA patients (Horton and Oliver 1976). We have subsequently enlarged our study of A and B locus HLA antigen and phenotype frequencies in cases of PA with neurological complications, the results of which are reported below. METHODS Patients Sixteen patients (8 male and 8 female) with neurological damage associated with vitamin Blz deficiency were studied; this represents an incidence of neurological disease in association with PA of approximately 13 ~. The haematological findings in the patients are shown in Table 1. The cases were selected from a series of PA patients under investigation at St. Bartholomew's Hospital, in whom the haematological criteria for diagnosis were based upon the demonstration of vitamin B12 malabsorption corrected by intrinsic factor in the absence of gastric surgery or small intestinal disease, megaloblastic bone marrow changes, a low serum vitamin B12 level, a full response to vitamin B12 replacement and in the majority of cases, autoantibodies to gastric parietal cells or intrinsic factor. Only patients with evidence of peripheral neuropathy, posterior column or pyramidal tract involvement for which no other cause could be found and in whom a partial or complete reversal of signs occurred in response to vitamin B12 therapy alone, were HLA-typed; cases in which distal paraesthesiae or diminished ankle jerks were present as an isolated finding were not included in the study. The clinical and neurological features are summarised in Table 2. HLA typing HLA typing was performed using platelet complement fixation (Cotombani, Colombani, Dehay and Dausset 1970) and standard NIH lymphocytotoxicity sera defining 11 antigens of the A locus and 16 antigens of the B locus, as well as the complex specificities "4a" and "4b". Control groups for HLA antigen frequencies consisted of 53 patients suffering from PA without neurological disease and 60 healthy staff members of St. Bartholomew's Hospital.
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