A case of aortitis syndrome and IgA nephropathy: possible role of human leukocyte antigens in both diseases.

A 51-year-old woman, who had both aortitis syndrome (Takayasu arteritis) and IgA nephropathy, presented with hypertension, fever, a high erythrocyte sedimentation rate, high C-reactive protein and serum IgG levels, proteinuria, and renal dysfunction. Renal arteriography showed stenosis and poststenotic dilatation at the origin of the right renal artery, as well as tortuosity of the left renal artery branches and marked atrophy of the left kidney. Renal biopsy showed IgA nephropathy with deposits of IgA, C3, and fibrinogen in the glomeruli and arteriolosclerosis. The present patient had human leukocyte antigen (HLA)-B 52, which is reported to be related to the aortitis syndrome, as well as HLA-DR 4, which is possibly related to IgA nephropathy, suggesting that HLA status may be involved in the pathogenesis of both diseases.

[Relationship between postoperative prognosis and preoperative immunological factors in aortitis syndrome].

Valve detachment or pseudoaneurysm is a well known complication of surgical treatment for cardiovascular disease due to aortitis syndrome. Although the preoperative management of inflammation by steroid therapy is very important, occasionally, the operation in active phase might be recommended because of progressive heart failure or impending rupture of aortic aneurysm. The pathology of aortitis syndrome is related to immunological abnormality, but there has been little information concerning the immunological factors. In order to evaluate the relationship between immunological factors and surgical results in patients with aortitis syndrome, immunological examination was obtained before surgery in 12 patients. Cardiovascular lesions due to aortitis syndrome were aortic regurgitation in 6 patients, annuloaortic ectasia in 1 patient, aortic arch aneurysm in 1 patient, mitral regurgitation in 2 patients, and coronary artery disease in 2 patients. Hospital mortality including initial operative death was not found. However, 6 late death (50%) occurred at late time with the mean of 23.8 months because of severe complications such as valve detachement or pseudoaneurysm after operation. In a comparison of the preoperative immunological values between survival group and late death group, immunoglobulins such as IgG, IgA, C3 and C4 were significantly higher in late death group. According to the recurrence of inflammation, the patients were divided into three groups. Group A included 3 patients who remains in active phase after initial operation in active phase. Group B included 3 patients who changed to active phase after initial operation in inactive phase. Group C included 6 patients who remains in inactive phase after initial operation. In a comparison among 3 groups, IgG and C4 showed no significant difference. However, IgA and C3 of group C were significantly lowest among three groups. This outcome is considered to be related to existence of latent inflammation. At operation, insertion of rigid prosthesis to fragile position due to latent inflammation may stimulate immunological reactions. We conclude that the preoperative values of the immunological factors, especially IgA and C3, are reliable predictors in postoperative prognosis.

Cellular immunocompetence in aortitis syndrome.

Cellular immunocompetence was investigated in 17 cases of aortitis syndrome (3 active, 14 inactive stage). Both the active and inactive groups demonstrated significantly lower interleukin-2 (IL-2) production than healthy volunteers. The active aortitis syndrome group produced significantly more interleukin-1 beta (IL-1 beta) than the inactive group. The proportion of CD11b+ CD8+ cells was significantly lower in the active aortitis syndrome group. Further, the proportions of CD11b- CD8+ cells and CD57+ CD16- cells in the aortitis syndrome patients were significantly higher than the healthy volunteers. These results suggest that there are intrinsic qualitative abnormalities in the T cells that produce IL-2 in aortitis syndrome. Pathogenesis of aortitis syndrome is considered as follows: during the active stage, diminished IL-2 production impairs differentiation and proliferation of suppressor T cells, thus creating abnormalities in the inhibitory functions of immunoregulation and promoting the proliferation of cytotoxic T and natural killer (NK) cells. This presumably initiates inflammation of the aorta and/or artery.

Clinical analysis of steroid-responsive sensorineural hearing loss.

In order to clarify general clinical features, characteristics of hearing level fluctuation, and therapeutic strategy in steroid-responsive sensorineural hearing loss, we conducted clinical analysis in the cases which were registered based upon the diagnostic criteria proposed by Kanzaki in 1981. The results obtained were as follows: (1) Disregarding steroid-responsiveness, both ears were impaired in all cases. (2) Female predominance and middle aged onset were found. (3) The underlying immunological abnormality could exist even in the cases without systemic autoimmune disease. (4) The mean incidence in acute hearing change was about once a year in low-frequency area and once 2 years in mid- and high-frequency areas. (5) The mean value of maximum hearing level fluctuation during follow-up period was about 35 dB. (6) The final prognosis of hearing was relatively excellent. (7) By the supplemental administration of Sairei-to for more than 2 years, the maintenance dose of prednisolone was reduced in 80% of the subjects without any significant deterioration of hearing.

HLA antigens in Indian population with non-specific aortoarteritis.

HLA typing of Class I antigens (HLA - A & -B loci) was done for 65 patients suffering from nonspecific aortoarteritis, in Indian population. The diagnosis of these patients was based on clinical findings and confirmed by angiographic studies. Decreased phenotype frequency of HLA-A19 (p less than 0.005, relative risk 0.28), increased frequency of HLA-B5 (p less than 0.005, relative risk 2.46) and B21 (p less than 0.005, relative risk 3.25) was observed when compared with the control group. A decreased frequency of two other alleles of B locus i.e. B35 (p less than 0.005, relative risk 0.27) and B40 (p less than 0.05, relative risk 0.04) was seen in patient group as compared to control. The data indicate the possible association of HLA-B5 and B21 antigens with the nonspecific aortoarteritis.

Immunologic studies in patients with Takayasu's arteritis. III. Immunoregulatory changes.

Study of cellular immune function in 14 patients with Takayasu's arteritis (TKA) revealed markedly decreased active E rosettes and CD4+ cells and slightly diminished CD8 + and autologous rosette-forming T cells. They were also found to have decreased production of interleukin-2 and decreased response to interleukin-1. Patients with active disease were also found to have decreased response to IL-2. Conversely, patients with inactive disease were found to have a normal response to interleukin-2. Patients with TKA, whether active or inactive, had normal production of interleukin-1, normal concanavalin-A-induced and spontaneously expanded suppression, normal NK cell function and normal enhancement of NK cell function by interleukin 2. The findings indicate that the immunoregulatory disturbance of TKA is different from that occurring in connective tissue disorders.

Takayasu's arteritis: a pathogenetic role for cytotoxic T lymphocytes?

Takayasu's arteritis is an inflammatory panarteritis of unknown aetiology affecting large elastic arteries. We examined a segment of abnormal common carotid artery removed at by-pass surgery from a 23-year-old man with typical angiographic features of Takayasu's arteritis. Using monoclonal antibodies we were able to demonstrate marked infiltration of the arterial wall with OKT8 positive lymphocytes (suppressor/cytotoxic cells) but not with OKT4 positive lymphocytes (helper cells). Studies of circulating lymphocytes showed increased numbers of "activated" cells and increased in vitro cytotoxicity against cultured human umbilical cord endothelial cells, compared to normal lymphocytes. Cellular immunological mechanisms may play an important role in the pathogenesis of Takayasu's arteritis, possibly through the direct action of cytotoxic T cells on large elastic arteries.

Immunologic studies in patients with Takayasu's arteritis. II. Effects of serum on lymphocyte functions in vitro.

Natural lymphocytotoxic antibodies, circulating immune complexes and their effect on in vitro blast transformation of normal cells were studied in 24 patients with Takayasu's arteritis. Sera with Takayasu's arteritis lacked lymphocytotoxic antibodies, had an inhibitory effect on the formation of EA and EAC rosettes and interfered with normal lymphocyte function in vitro. The absence of lymphocytotoxic antibodies, together with the other epidemiological and histocompatibility studies, would support the notion that Takayasu's arteritis and temporal arteritis are two distinct entities.

HLA-DR MT and MB antigens in Takayasu disease.

Recent studies on the pathogenesis of Takayasu disease have focussed on the participation of genetic factors, and HLA analysis has confirmed the close relationship between Takayasu disease and HLA Bw52. In an attempt to investigate the association of immune response gene with the disease, HLA-DR (DR-1, -2, -3, -4, -5, -w6, -7, -w8, -w9, -w10), MT (-1, -2, -3), MB (-1, -3) antigens were studied in 52 patients with Takayasu disease and the data compared with findings in healthy Japanese. As there were no statistical differences between the two groups in the frequencies of all these antigens, genetic factors in Takayasu disease may be much more closely associated with B than with D loci.

HLA and clinical manifestations in Takayasu disease.

In previous studies on HLA antigens in patients with Takayasu disease, we found a statistically high frequency of haplotype Bw52-Dw12. Clinico-pathological conditions of this disease observed for 85 +/- 3 months were compared between 29 patients with (positive group) and 39 patients without this haplotype (negative group), among 82 patients with Takayasu disease. Blood sedimentation rate and C-reactive protein exhibited statistically significant high figures in the positive group as compared with those in negative group, while no difference were seen in rheumatoid arthritis test, antistreptolysin-0 titer, anti-DNA antibody, levels of circulating immune complexes, platelet aggregation, although all revealed high levels in the positive group. Pulmonary disorders were more frequent in positive group. Fourteen patients (48%) in the positive group and 5 (13%) in the negative group had abnormalities in the aortic valve (p less than 0.01). In 14 patients in the positive (38%) and 5 in the negative (13%) groups, the systolic blood pressure was over 140 mmHg (p less than 0.01). Four patients in the positive (17%) and one in the negative groups (3%) were blind (p less than 0.01). These data suggest that in patients with a haplotype of Bw52-Dw12, there is a greater likelihood of an active inflammatory state and a rapid progression of these morbid conditions.

Immune complexes in Takayasu's arteritis.

We examined sera and Fc receptor-bearing lymphocytes from peripheral blood of patients with Takayasu's arteritis for the purpose of investigating the presence of immune complexes (IC). IC in sera were assayed by solid-phase conglutinin-binding test. Seven of 29 patients exceeded the normal range of circulating IC. IC combined with Fc receptors were estimated by enumerating EA-RFC. EA-RFC of lymphocytes from patients with Takayasu's arteritis were 13.0% and those of normal controls were 29.1%. Low EA-RFC in the patient group increased significantly when lymphocytes were incubated with EA after rising lymphocytes with medium at 37 degrees C. On the contrary, EA-RFC from healthy subjects did not increase after rinsing cells. These findings indicate that IC combined with Fc receptors and hindered EA rosette formation and that rinsing cells with medium at 37 degrees C removed IC from Fc receptors. Comparable results were obtained by a membrane immunofluorescence method using FITC-conjugated anti-human immunoglobulin. In order to confirm that EA rosette formation was really blocked by IC, lymphocytes from a healthy donor were incubated with heat-aggregated human IgG. Incubating cells with IgG aggregates caused reduction of EA-RFC and these lymphocytes restored their ability to form rosettes with EA by rinsing cells with medium at 37 degrees C. In conclusion, we could confirm the presence of IC both in sera and on lymphocyte Fc receptors in some cases of Takayasu's arteritis.

[Immunologic studies in Takayasu's arteritis. I. Circulating antibodies to mycobacterial products and circulating immune complexes]. / Estudios inmunológicos en la arteritis de Takayasu. I. Anticuerpos circulantes a productos de micobacterias y complejos inmunes circulantes.

Takayasu's arteritis (TA) is an arteriopathy of unknown origin that affects young women preferentially and shows a characteristic geographical distribution. Previous reports suggested immune related pathogenesis and certain relationship with mycobacterial infections. Therefore we look for humoral antibodies against four different mycobacterial products as well as for immune complexes which react with human Clq, in 24 patients suffering TA in chronic inactive phase (22) and with relapsing erythema nodosum (2). No single case showed circulating immune complexes and only 3 (12.4%) had antimycobacterial antibodies, including a young female with relapsing erythema nodosum. The presence of immunopathogenic mechanisms in chronic TA is not supported in this work. Further studies using different approaches are now in progress.