The life cycle of antibody-forming cells. I. The generation time of 19S hemolytic plaque-forming cells during the primary and secondary responses.

The generation, time of cells synthesizing 19S antibody was measured during the exponential phase of the primary and secondary immune responses. Using a plaque-forming cell assay together with a double label isotope method, the duration of the generation time was found to be about 13 hr, that of the S period was about 8 hr, and that of G-1 and G-2 were about 3 and 2 hr, respectively, in both immune responses. Previous work was confirmed showing that all plaque-forming cells observed during the exponential phase of the immune responses incorporate labeled thymidine, and therefore take part in proliferation. These results were obtained at points during both responses when the doubling time of the PFC was observed to be 6-7 hr. This finding makes untenable the hypothesis that the rate of appearance of PFC equals the rate of proliferation of these cells. A hypothesis is presented to account for these findings and to serve as a basis for further experiments.

A new strategy of drug treatment in NSAID-unresponsive ankylosing spondylitis: combination of pamidronate and methylprednisolone monthly intravenous infusions on the background of a combination of disease modifying drugs sulfasalazine and methotrexate.

OBJECTIVES: To assess short term efficacy and tolerability of a therapeutic strategy in patients with ankylosing spondylitis (AS) unresponsive to nonsteroidal anti-inflammatory drugs (NSAIDs) or coxibs and unable to take anti-tumour necrosis factor-alpha (anti-TNFalpha) biological treatment. METHODS: Established AS patients were given a background treatment consisting of subcutaneous injections of methotrexate weekly (MTX, dose stepped up to a maximum of 20 to 25 mg), weekly 12-16 mg of methylprednisolone orally 30 mts before methotrexate dose (for nausea prevention), sulfasalazine (SSZ, 1 gm orally twice per day) with folic acid supplementation (5 mg daily except on the day of MTX). Additionally, they were given monthly cycles of intravenous (IV) methylprednisolone 'pulse' (MPP) and pamidronate infusions (MPP 500 mg 3 consecutive days + pamidronate 60 mg in a slow IV infusion on day 2 of the MPP infusion). A minimum of six treatment cycles at monthly intervals were given. Adjunct treatment consisted of 1 gm elemental calcium supplementation, paracetamol 650 mg 'as-and-when-required' for symptomatic pain relief, amitriptyline 10 mg 2 hours before bed time daily. RESULTS: Of a total of 46 intent-to-treat patients, 39 patients achieved ASAS-20 and BASDAI-50 response (85%, 95% CI, range 71% to 94%); 7 (15 %) patients failed to improve. The expense involved in 6 months of treatment was approximately 10-fold less than anti-TNFalpha treatment over the same period of time. CONCLUSION: For AS patients unresponsive to standard NSAIDs/coxibs and unable to take anti-TNF biological agents a combination therapeutic strategy showed efficacy and good tolerability in a majority of patients evaluated over a short-term.

Henoch-Schönlein's purpura in adults versus children/adolescents: A comparative study.

OBJECTIVE: To assess the possible differences in etiological and clinical factors between children/adolescents (< or = 20 years) and adults (> 20 years) with Henoch-Schonlein purpura (HSP). METHODS: A retrospective-cum-prospective study of consecutive patients with HSP who presented to our teaching hospital over 5 years. Patients were classified as having HSP according to the criteria proposed by Michel et al and the ACR criteria. RESULTS: 102 patients (43 of all patients being male and 59 female) were classified as having HSP; 20 of the patients were adults (mean age 32.1 +/- 11.7 years) and 82 were children/adolescents (mean age 6.2 +/- 2.6 years). We were unable to identify any precipitating event in 40% of the adults and 37% of the children/adolescents. The frequency of previous drug treatment and of previous upper respiratory tract infection was similar in both groups. At symptom onset, palpable purpura was the chief clinical manifestation in both groups. However, renal involvement, in all its aspects, was more frequent and severe in adults. Adults also had a higher frequency of diarrhoea (with or without occult blood) and leucocytosis, but a lower frequency of thrombocytosis. The frequency of joint manifestations, nausea, vomiting, malena/hematochezia and intussuseption was equal in both groups. Adults required more aggressive therapy, and had a longer hospital stay (10.2 vs. 4.3 days). The outcome was relatively worse in adults, with complete recovery in 18 adults (90%) compared to 81 children/adolescents (98.8%) after a mean +/- SD follow up of 2.8 +/- 1.7 and 2.4 +/- 1.3 years, respectively. CONCLUSION: In adulthood, HSP is a more severe clinical syndrome, with a higher frequency of diarrhoea and renal involvement. Adults also require aggressive treatment more frequently and have a longer hospital stay.

Refractory thrombocytopenia in antiphospholipid syndrome.

Thrombocytopenia is the second most common manifestation of antiphospholipid syndrome (APS). It is found in approximately 22% of the patients with this disease. Often it is not severe, platelet counts usually range between 50 x 10(9)/L and 150 x 10(9)/L without bleeding problems. Yet, it does not protect patients against thrombotic events. It rarely requires treatment and, due to similarities to idiopathic thrombocytopenic purpura (ITP), similar treatment rules usually apply. In this report two patients with APS are described who presented with severe thrombocytopenia that did not respond to standard treatment regimen namely glucocorticoids (GC) followed by intravenous immunoglobulin therapy (IVIG). Splenectomy had to be resorted to relieve the condition.

Association of type I (insulin-dependent) diabetes mellitus, autoimmunity, antinuclear antibody, and membranoproliferative glomerulonephritis.

In a large series of patients with insulin-dependent diabetes mellitus who were screened for autoantibodies, two patients were positive for antinuclear antibodies. Both of these patients developed severe renal disease with the renal biopsy findings of membranoproliferative glomerulonephritis. Multiple autoantibodies and circulating immune complexes were demonstrated in their sera. There was evidence suggesting complement consumption. This article illustrates that immune complex glomerulonephritis can occur in some patients with IDDM, particularly in those with antinuclear antibody and polyendocrine involvement, and that renal biopsy in such cases may have prognostic and therapeutic importance.

HIV serosurveillance among prostitutes and patients from a sexually transmitted diseases clinic in Delhi, India.

Screening of 701 prostitutes in Delhi for HIV antibodies by a competitive ELISA test and supplementary Western blot test showed that only one of them was infected. Of the 4,572 samples from the patients attending a sexually transmitted disease clinic in Delhi, none showed evidence of HIV infection. In contrast to this low frequency of HIV infection in Delhi, a much higher frequency has been reported to the Indian Council of Medical Research from major metropolitan centers on the coast of India, namely, Bombay and Madras and their surrounding areas. It is possible that the infection is making inroads from these coastal areas to the interior of the country.

Human immunodeficiency virus infection in the blood donors of Delhi, India.

In the present study, blood from paid and unpaid donors was screened for the presence of HIV infection using a competitive ELISA test. None of the 8,000 unpaid donors but 4 (0.23%) of the 1,700 paid donors showed evidence of HIV infection. All of these four ELISA-positive samples were confirmed by the Western blot test. The present study indicates that HIV infection has entered the group of paid donors in the Delhi metropolitan area. Careful donor screening, discouraging use of paid donors, and stringent screening of donated units of blood has become mandatory in India to prevent HIV transmission through blood and blood products.

PIP: In Delhi, India, researchers collected sera from 1700 paid blood donors between January-February 1989 and from 8000 voluntary blood donors between September 1, 1988-February 28, 1989. Laboratory personnel screened all the sera for HIV antibodies using a competitive ELISA test. Any samples found to be reactive were tested again using the ELISA technique. Laboratory personnel determined reactivity a 2nd time in 4 samples. They confirmed that these 4 samples were positive for HIV by the Western blot test. The 4 positive samples came from paid donors (.23%), while no positives occurred in the volunteer group. Characteristics of the paid donors included male, 50% unemployed, illiterate, and median age of 28 years. 95% of the volunteers were males. Also volunteers were generally literate and educated. 3 of the 4 HIV positive donors were daily-wage unskilled laborers who went from city to city seeking employment. To sustain themselves or support their families, they would donate their blood often. All 3 have had sex with prostitutes. The 4th donor could not be found. Even though the prevalence of HIV is low among prostitutes in INdia, they are the largest risk group and prevalence is climbing. Since paid blood donors are usually transient, they can spread HIV to prostitutes of other cities as well as to recipients of their donated blood. 2 possible targets of intervention include educating the public to not accept blood from professional blood donors since their blood is not tested for HIV and educating prostitutes on methods of prevention of HIV infection.

C3b receptor (CR1) genomic polymorphism in rheumatoid arthritis. Low receptor levels on erythrocytes are an acquired phenomenon.

The number of complement receptor 1 (CR1, CD35) molecules on erythrocytes is genetically determined by two codominant alleles. The numerical expression of CR1 on erythrocytes correlates with a HindIII-RFLP or CR1 gene using CR1-1, a complementary DNA probe. We have found low CR1 on erythrocytes in patients with rheumatoid arthritis (RA) in an Indian population. Low levels in RA patients may be acquired or genetically determined. Fifty-two patients with RA, 48 nonrelated healthy subjects and 19 consanguineous relatives of patients were genotyped. CR1 numbers on erythrocytes were quantitated by the enzyme-linked immunosorbent assay using monoclonal anti-CR1 antibody. Normal subjects and patients were followed up for a period of 6 months to evaluate the stability of their CR1 expression. The gene frequency for allele H and L (7.4- and 6.9-kb HindIII restriction fragment, respectively), which correlated with high and low expression of CR1 on erythrocytes was 0.77 and 0.23 in the normal controls. Gene frequency in RA patients was 0.78 and 0.22 for H and L allele, which did not differ significantly from either controls or relatives (0.80 and 0.20 for H and L allele, respectively). However, RA patients expressed fewer CR1 on erythrocytes within each genotype than their relatives and controls. CR1 on erythrocytes were found to be stable in consecutive samples in controls. In RA patients, the number varied between low and high during the course of the disease. The variation in number was significantly correlated (p < 0.05, r = -0.85 to -0.98) with disease activity as monitored by erythrocyte sedimentation rate. Our results suggest that low levels of CR1 on erythrocytes in patients with RA are not inherited, rather they are acquired during the course of the disease.

Polymorphism of HLA-DRB, -DQA1, and -DQB1 in rheumatoid arthritis in Asian Indians: association with DRB1*0405 and DRB1*1001.

We investigated the DRB, DQA1, and DQB 1 polymorphism and haplotypes in sporadic and familial RA subjects of Asian Indian origin by PCR oligotyping using biotinylated SSOPs. Molecular subtyping of DRB 1*04 in RA patients showed strongest association with highest relative risk with DRB 1*0405, followed by DRBI*0401. A significant decreased frequency of DRBI*1502 was observed in patients compared to controls (chi 2 = 4.5). Among other alleles, DRBI*1001 was found to be significantly increased. A total of 73.3% of patients carried the shared sequence of the third HVR (67-74) of DRB1 domain compared to its presence in only 37.6% of controls. A significant number of patients carried DR4 haplotypes on DQBI*0302 (58%) as against DQBI*0301 which was present only on 10.5% of the haplotypes. When compared to controls, the difference was significant for the latter allele only. Few unique DRDQ haplotypes were observed in Asian Indians. Among DR-DQ haplotypes, DRB1*0401-DQB1*0302 gave the highest risk whereas DRB1*0403-DQB1*O301 was negatively associated. Alleles with negative charge at position 70 confer protection or are negatively associated with RA whereas among the associated alleles, glycine at position 86 resulted in higher risk than those with valine at this position. A heterogenous association of DQB1 alleles with DR4 subtypes, influencing susceptibility to RA, suggests the DQB locus is not primarily associated with RA and susceptibility lies in the sequence 67-74 of the DRB1 loci.

Lowered expression of C3b receptor (CR1) on erythrocytes of rheumatoid arthritis patients.

The number of C3b receptors (CR1) on erythrocytes (E) has been quantitated by whole cell enzyme-linked immunosorbent assay (ELISA), using a monoclonal anti-CR1 antibody, in 46 healthy individuals as controls, 58 having rheumatoid arthritis (RA) and 3 hereditary angioedema patients. The mean value of CR1 in RA (381/E) was significantly lower (p < 0.001) when compared to normal controls (646/E). In hereditary angioedema patients CR1 numbers (620/E) were found to be comparable to normal values. No significant difference was found between normal male (708/E) and female (598/E) subjects. Among the patient groups, those on steroid therapy (352/E) showed no change compared to others not receiving such therapy (408/E). The cumulative frequency curve of CR1 in the normal population showed maximum inflection at 32% and 82%. This led us to conclude that there is a trimodal distribution of receptors in the control population. Such a contention is well supported by frequency histogram, when a small group interval (0-50) was chosen. However, if large group intervals (0-100 or 0-150) were considered, a very close approximation to unimodal pattern was obtained. The factors actually contributing to low receptor numbers are yet to be elucidated.

HLA antigens in type I (insulin-dependent) diabetes mellitus in North India.

Fifty-four North Indian patients with Type I (Insulin-Dependent) diabetes mellitus who were aged 30 yr or under at onset were HLA-typed. The frequencies of HLA-BW21, BW35, and A28 were significantly increased and that of HLA-B7 was significantly reduced. On correction for the number of antigens tested, only the difference observed with HLA-BW21 for positive association and B7 for negative association remained statistically significant. HLA-B8, B15 and B18 did not demonstrate any significant association with IDDM in this series of patients. The results of the study further emphasize the well recognized race specificity in HLA antigen distribution in normal population as well as disease states. This association of HLA-BW21 with IDDM is the first report from North India.

Arthritis associated with tuberculosis.

There has been a resurgence in tuberculosis (TB) worldwide. Approximately 2 billion people have latent infection, 8 million would develop active TB annually, and 2-3 million would die due to TB. With this resurgence, cases with extrapulmonary TB have also shown an increase. Approximately 10-11% of extrapulmonary TB involves joints and bones, which is approximately 1-3% of all TB cases. The global prevalence of latent joint and bone TB is approximately 19-38 million.TB arthritis most commonly manifests as a monoarthritis of weight-bearing joints in the hip or the knee. Oligo- or polyarticular presentation is not rare and may cause diagnostic confusion with inflammatory arthritis. Owing to the low incidence in developed countries, the diagnosis of joint and bone TB is often delayed. A high degree of sensitivity to this diagnosis would prevent delays, permitting prompt institution of anti-TB therapy and preventing irreversible joint damage. Despite advances, confirmation of diagnosis still relies on lengthy microbiological techniques or invasive biopsy. Due to the frequency of isoniazid resistance, initial treatment at present typically includes a combination of four drugs: isoniazid, rifampicin, pyrazinamide and streptomycin or ethambutol. Antimicrobial therapy should be of at least 9 months duration, longer in children and immunocompromised hosts. Surgical procedures should be restricted to joints with severe cartilage destruction, large abscesses, joint deformity, multiple drug resistance or atypical mycobacteria.

Gold-induced hypersensitivity pneumonitis in a patient with rheumatoid arthritis.

A case of gold-induced hypersensitivity pneumonitis in a patient with rheumatoid arthritis is reported. Its differentiation from interstitial pulmonary fibrosis associated with rheumatoid arthritis is discussed and the low T4/T8 ratio in the bronchoalveolar lavage fluid of these patients is highlighted.

D-penicillamine-induced acute hypersensitivity pneumonitis and cholestatic hepatitis in a patient with rheumatoid arthritis.

Acute hypersensitivity pneumonitis is not a known side effect of D-penicillamine. Also, there are only a few reports of cholestatic hepatitis caused by this drug. The present report describes a case of rheumatoid arthritis where these manifestations appeared in the same patient ten days after the institution of D-penicillamine therapy. The etiological relationship with the drug was established, inadvertantly, by its accidental intake by the patient 5 months later with the reproduction of the same manifestations.

Hypergammaglobulinemic purpura of Waldenström: report of 3 cases with a short review.

Benign hypergammaglobulinemic purpura of Waldenström (HGPW) is an uncommon cause of non-thrombocytopaenic purpura that may create diagnostic difficulties. The presence of constitutional symptoms associated with prominent immunological abnormalities may raise alarm, leading to extensive and often unnecessary investigations. This report describes 3 young women with HGPW. Clinical features were characterised by recurrent episodes of bilateral asymmetrical palpable purpuric lesions on the lower extremities that were precipitated by a prolonged increase in hydrostatic pressure (e.g. prolonged standing, tight stockings etc.) associated with constitutional features. In one patient the condition was secondary to Sjögren's syndrome with type IV renal tubular acidosis. Laboratory abnormalities included a persistently elevated erythrocyte sedimentation rate, marked polyclonal hypergammaglobulinemia, and high titers of rheumatoid factor and anti-nuclear antibody of the anti-SSA (anti-Ro)/anti-SSB(anti-La) subsets. This topic is reviewed briefly with the emphasis that in its 'primary' form this condition could be considered a 'benign' systemic immunoinflammatory disease that requires neither extensive investigations nor any aggressive form of therapy. Greater awareness of HGPW may increase the frequency of its diagnosis, especially in the patient group with non-thrombocytopenic purpura or the so-called cutaneous vasculitic syndromes with 'palpable purpura'.

Trigeminal and peripheral neuropathy in a patient with systemic sclerosis and silicosis.

The unusual occurrence of cranial (trigeminal) and peripheral neuropathy in a case of progressive systemic sclerosis (PSS) is described. The possible association of PSS with silicosis is also discussed.

Bilateral recurrent laryngeal nerve palsy in systemic lupus erythematosus.

An unusual occurrence of bilateral recurrent laryngeal nerve palsy as an initial manifestation of systemic lupus erythematosus (SLE) is described. The patient had positive lupus anticoagulant (LAC) and high titers of anti-dsDNA antibody. She showed rapid improvement following intravenous pulse dexamethasone.

Differentiation of patients with rheumatic fever from those with inactive rheumatic heart disease using the artificial subcutaneous nodule test, myocardial reactive antibodies, serum immunoglobulin and serum complement levels.

Thirty patients with acute rheumatic fever, and 20 with inactive rheumatic heart disease were studied in order to determine parameters which differentiate the two groups. Subcutaneous nodules developed following the subcutaneous injection of autologous blood in 16 of 26 patients with rheumatic fever but in none of the 20 with inactive rheumatic heart disease (P = 0.00001). Myocardial reactive antibodies were found in 14 of 30 patients with rheumatic fever, and in 4 of 20 with inactive rheumatic heart disease (P = 0.0505). Significantly higher values of IgG (P less than 0.001), IgA (P less than 0.01), C3 (P less than 0.001) and C4 (P less than 0.001) were observed in rheumatic fever patients. There was no significant difference in IgM levels. A combination of three variables (artificial subcutaneous nodules, IgA, and C3) had a sensitivity of 87% and a specificity of 100% for rheumatic fever. A combination of two variables (artificial subcutaneous nodules and IgA) had a sensitivity of 84% and a specificity of 100% for rheumatic fever.

Prognostic significance of renal angiitis in systemic lupus erythematosus (SLE).

Analysis of 80 cases of SLE with renal involvement revealed the following. Angiitis involving arterioles and interlobular arteries was observed in 17 out of 42 cases with diffuse proliferative lupus GN. This was not observed in other types of lupus GN. Out of 17 cases of angiitis, 7 were complicated by thrombosis. Irregular deposits of immunoglobulins and complement were demonstrated in the vessel walls and in luminal thrombi and suggested an immune-complex origin. Fibrinogen was also demonstrable frequently. The vascular lesions were associated with severe glomerular and tubulointerstitial injury and a poor prognosis. A relatively favorable outcome was observed in SLE without renal angiitis.