Increase of IgA-bearing lymphocytes in peripheral blood from patients with IgA nephropathy.

Aberration of IgA-bearing B lymphocytes in patients with IgA nephropathy has been investigated. Twelve patients with IgA nephropathy demonstrated a marked increase of IgA-bearing lymphocytes in peripheral blood, while ten patients with chronic proliferative glomerulonephritis without mesangial deposition of IgA showed normal amounts of IgA-bearing lymphocytes. The increase of IgA-bearing lymphocytes reflected that of IgA-producing lymphocytes, since lymphocytes obtained from patients with IgA nephropathy restored a high percentage of IgA-bearing cells in vitro after treatment with trypsin. Quantitation of IgA-bearing lymphocytes in peripheral blood is a useful method for screening of patients with IgA nephropathy.     

Increase of IgA specific helper T alpha cells in patients with IgA nephropathy.

Patients with IgA nephropathy show an emergence of IgA dominant circulating immune complexes (CIC) as well as increased levels of serum IgA and/or IgA bearing peripheral blood lymphocytes. In order to elucidate immunological aberrations responsible for the increased IgA synthesis in such patients, quantitative and qualitative analysis was performed on T alpha cells which have been recently identified as possessing IgA specific helper activity on human B cells. Three different methods were employed to quantitate T alpha cells. These methods included a rosette formation of T cells with either bovine red cells coated with the IgA fraction of anti-bovine red cell antiserum or those coated with TNP and anti-TNP IgA antibody, and an analysis of T cells combined with fluorescein conjugated human IgA myeloma protein. T alpha cells were sorted by a fluorescence activated cell sorter and co-cultured with a B cell rich fraction to evaluate whether there is a qualitative difference in IgA specific helper activity between patients and healthy adults. T alpha cells were significantly increased in patients with IgA nephropathy while there were no significant changes in patients with chronic proliferative glomerulonephritis without mesangial deposition of IgA. There was no qualitative difference in IgA specific helper activity of T alpha cells between patients and healthy adults. It is suggested that increased levels of T alpha cells in patients with IgA nephropathy may be responsible for increased synthesis of IgA in such patients.     

Increase of IgA-specific switch T cells in patients with IgA nephropathy.

Enumeration and functional analysis of CD4+ T cells with receptors for the Fc portion of IgA (i.e. T alpha 4 cells) in the peripheral blood of patients with IgA nephropathy, their relatives and age-matched controls were performed to elucidate polyclonal activation of IgA production in this disease. Enumeration of T alpha 4 cells was performed by a fluorescence activated cell sorter, and functional analysis was carried out by separation of T alpha 4 cells, and IgM-, IgA- and IgG-bearing lymphocytes using panning methods followed by cultures of these cells for 7 days with pokeweed mitogen. There was a significant increase in the amount of peripheral blood T alpha 4 cells in patients with IgA nephropathy and their relatives. T alpha 4 cells specifically enhanced the switch of IgM-bearing cells to IgA-bearing cells, and this switch activity was inhibited by addition of human myeloma IgA. It is suggested that T alpha 4 cells may be responsible for polyclonal activation of IgA production in IgA nephropathy.     

Induction of Fc receptors for IgA on murine T cell hybridoma by human monoclonal IgA and by high molecular weight IgA in IgA nephropathy.

A reproducible immunocyto-adherence assay has been developed to study the modulation of Fc receptors for IgA (Fc alpha R), using a murine T cell hybridoma (T2D4), which expresses Fc receptors for all known isotypes of secreted immunoglobulins. By using sheep red blood cells coated with the hapten 2-4-6 trinitrophenyl (TNP), as indicator cells, and a murine monoclonal IgA (MOPC 315) antibody with anti-TNP activity, we were able to study the Fc alpha R on T2D4 cells. We found that: (a) murine Fc alpha R can bind human monoclonal IgA, and this binding is isotype specific since it was inhibited by human monoclonal IgA but not by human monoclonal IgG or IgM; (b) the expression of murine Fc alpha R is unducible by human monoclonal IgA, and this effect is isotype specific since it is not observed with human monoclonal IgM or IgG (c) sera from patients with IgA nephropathy can also induce Fc alpha R expression; by contrast, no induction was observed with normal human sera, (d) in one serum from an IgA-nephropathy patient, the inducer factor was characterized by affinity chromatography on anti-IgA-Sepharose and by gel filtration: high molecular weight IgA, probably IgA aggregates or immune complexes were recognized to be responsible for the induction of murine Fc alpha R expression.     

IgA nephropathy associated with chronic hepatitis B virus infection in adults: the pathogenetic role of HBsAG

Five adult cases of IgA nephropathy associated with chronic hepatitis B virus infection were studied. Serum HBsAg and anti-HBc were present in five patients and HBeAg in four patients. Glomerular changes were typical of primary IgA nephropathy in four patients, and a mixed picture of IgA and membranous nephropathy was demonstrated in one patient. Immunofluorescence microscopy using polyclonal and monoclonal antibodies against HBsAg, HBcAg, and HBeAg revealed mesangial deposits of HBsAg in renal biopsies from four patients. One renal biopsy showed only mesangial and capillary HBcAg by polyclonal antiserum, and virus-like particles were demonstrated in the intramembranous electron-dense deposits on ultrastructural examination. Mesangial HBeAg was not detected in the renal biopsies from these patients with IgA nephropathy. As for the single patient with a mixed picture of IgA and membranous nephropathy, granular deposits of HBeAg with a distribution similar to IgG were detected in the glomerular capillary walls in addition to the mesangial deposition of HBsAg. These findings suggest that HBsAg rather than HBeAg may play a role of the pathogenesis in some of the adult patients with IgA nephropathy associated with chronic hepatitis B virus infection.     

Defective hepatic handling of IgA immune aggregates by mice with experimental IgA nephropathy.

In an experimental model of IgA nephropathy induced in mice by chronic immunization with dextran, we tested the hypothesis that a defect in the hepatic handling of IgA could be an important determinant in the deposition of IgA in the mesangium. In mice injected with 1-16 doses of 1 mg of dextran (after a preimmunization period of 21 days) the blood clearance of IgA immune aggregates was significantly delayed in relation to control animals, becoming normal at 24 injections. This alteration seems specific since the clearance of IgG aggregates was normal. The percentage of isolated hepatocytes with Fc receptors for IgA decreased significantly over the whole period of dextran immunization. The binding rate of 125I-IgA aggregates to hepatocytes of mice with 24 dextran injections was twice lower than that of control animals. By contrast, the percentage of Kupffer cells with IgA receptors increased over ensuing dextran injections. A progressive increase in the IgA blood levels and in the percentage of mice with mesangial IgA deposits was seen along the period of study. At 24 injections most animals presented moderate to intense mesangial proliferation and abundant electron-dense deposits. On the whole, these data suggest that the early impairment in the liver IgA clearance capacity observed in these animals could facilitate the presence of circulating immune complexes (IC) and their deposition in the mesangium. The increase in serum IgA, seen thereafter, together with the normalization of the IgA clearance capacity, suggest that other pathophysiological mechanism(s) (e.g. in situ IC formation or IgA polymers deposition) must also be involved in this model of experimental IgA nephropathy.     

Up-regulation of receptors for IgA on activated human B lymphocytes

Expression of receptors for the Fc part of IgA (Fc alpha R) by T lymphocytes was recently shown to be up-regulated after activation by T cell mitogens in the absence of IgA. We describe a similar increase on activated human B lymphocytes. Fc alpha R were determined by labelling with human secretory IgA (0.5 mg/ml) and flow cytometry analysis after staining with fluoresceinated goat anti-IgA or goat anti-secretory component F(ab')2 fragments. B-enriched cell suspensions were prepared from peripheral blood or tonsils and activated by Staphylococcus aureus Cowan I, anti-IgM antibodies or E. coli lipopolysaccharide. All three activators increased the percentage of Fc alpha R positive cells although only the former induced significant DNA synthesis. Finally recombinant interleukin 1 (10 nM) and interleukin 2 (10 IU/ml) but not interleukin 4 (300 units/ml) nor low-molecular-weight B cell growth factor induced an increase of Fc alpha R expression. The data show that Fc alpha R can be up-regulated on human B cells in the absence of exposure to IgA.     

Mucosal immune dysfunction associated with alcoholic IgA nephropathy.

We investigated the hypothesis that alcohol-induced changes of the immune system result in IgA nephropathy (IAN). Wistar rats were infused with liquid diet containing alcohol: "alcoholics." Control rats received an isocaloric diet with glucose instead of alcohol. IAN was diagnosed by mesangial IgA deposition. When compared to controls, serum IgA in alcoholic rats with IAN had a fourfold increase and a twofold increase in alcoholics without IAN. The intestinal lamina propria showed overall lymphocyte depletion in alcoholic rats. The decrease was not uniform for all the lymphocyte subgroups: it resulted in a relative increase in IgA-B cells in alcoholic rats with IAN but not in alcoholic rats without IAN. No significant differences were observed between alcoholic and control rats in the percentages of spleen lymphocyte subtypes. We suggest that dysfunction of the mucosal immune system may be related to the induction of IAN in chronic alcohol consumption.     

Subpopulations of T alpha cells in patients with IgA nephropathy: correlation between T alpha 4 cells and in vitro IgA production

T cells play important roles in the regulation of the immune system and are divided into subpopulations by various kinds of markers on the membrane surface. T cells with Fc-receptors for IgA are termed T alpha cells, and the properties of this cell population have been revealed in recent years. T alpha cells are increased in patients with IgA nephropathy and possess IgA specific helper activity. T alpha cells consist of two subpopulations, T alpha cells with OKT4 antigen (T alpha 4 cells) and with OKT8 antigen (T alpha 8 cells). To investigate the immunological aberrations in patients with IgA nephropathy, we detected immunoglobulin produced by peripheral blood lymphocytes and enumerated the numbers of T alpha cells (including both T alpha 4 and T alpha 8 cells). The numbers of T alpha 4 cells (but not T alpha 8 cells) and in vitro IgA production were increased in patients with IgA nephropathy (IgA nephropathy, mean 1.9%. Control, mean 0.8%. P = 0.0075). In addition, the numbers of T alpha 4 cells and the amount of IgA in the supernatant of lymphocyte cultures were positively correlated in these patients (P = 0.025. r = 0.3836). From the results in the present study, it was suggested that T alpha 4 cells might be related to immunological aberrations, such as an increase in IgA seen in patients with IgA nephropathy.     

Serum levels and in vitro production of IgA subclasses in patients with primary IgA nephropathy

Patients with primary IgA nephropathy have deposits of IgA1 in their kidneys, and increased plasma levels of macromolecular IgA1. Total serum IgA concentrations are frequently elevated, but studies on the subclass distribution have been few and conflicting. Several investigators found that production of IgA by peripheral blood lymphocytes in culture is increased. However, the distribution of the IgA subclasses produced has not been studied previously. We studied the serum IgA subclasses in 14 patients with IgA nephropathy, and found a significant (P less than 0.001) increase in IgA1 (3.71 +/- 1.34 mg/ml, mean +/- s.d.) compared with controls (1.77 +/- 1.10 mg/ml). Serum IgA2 was not different in patients and controls. The ratio of serum IgA1 to total IgA was also significantly (P less than 0.001) higher in patients (92.2 +/- 4.9%) than in controls (80.2 +/- 6.6%). Studies of immunoglobulin production by peripheral blood mononuclear cells showed a significant increase in IgA1 synthesis, expressed as a fraction of total IgA synthesis in unstimulated cultures (P less than 0.05) and in PWM stimulated cultures (P less than 0.01). Polymeric IgA and polymeric IgA1 production were not higher in patients than in controls. IgM production in unstimulated cultures was significantly (P less than 0.05) higher in patients than in controls. Together with the observed deposition of exclusively IgA1 in the mesangium, our results indicate that patients with IgA nephropathy preferentially produce antibodies of the IgA1 subclass.     

T-cell dysfunctions in IgA nephropathy: specific abnormalities in the regulation of IgA synthesis

This work was undertaken to determine the cellular abnormalities that could explain the high levels of serum IgA frequently found in patients with IgA nephropathy. Seventeen control subjects and twenty-seven patients who had received no therapy were studied. After in vitro pokeweed mitogen (PWM) stimulation, significantly higher amounts of IgA were produced by peripheral blood mononuclear cells (PBM) of patients when compared with those of the control group (560 +/- 97 vs 231 +/- 57 ng/ml, P less than 0.0025). No differences were observed in the synthesis of IgG and IgM. Twenty out of twenty-seven patients presented an increase in the percentages of OKT4+ cells (mean + 2 SD), in relation to the control group, with normal or elevated percentages of OKT8+ cells. The OKT4+/OKT8+ cell ratio was elevated in 12 out of 27 patients. All patients presented some abnormality in the generation of IgA-specific suppressor cells at variable doses of concanavalin A (Con A) on in vitro PWM-stimulated culture of PBM. In both assays low doses of Con A (2.5 micrograms/ml) induced a certain suppression of IgA synthesis in patients that was not observed in the majority of the control group. At these doses some patients also showed an enhancement in the synthesis of IgG and IgM. On the contrary, higher doses of Con A (50 micrograms/ml) produced significantly less IgA suppression than the controls. Normal IgA-suppression values were found at 10 micrograms/ml of Con A. T cells obtained from patients were significantly more efficient than T cells from controls in providing IgA-helper activity for normal allogeneic enriched B cells (P less than 0.025) in PWM-stimulated cocultures. These results show that patients with IgA nephropathy present, after mitogen stimulation in vitro, a specifically increased production of IgA as well as an augmentation in the activity of IgA-helper T cell and a deregulation on IgA-suppressor T-cell function. According to these data, it is suggested that the alteration observed in helper T cells might precede that of suppressor T cells. These immunoregulatory abnormalities might contribute to the pathogenesis of the disease.     

Etiology of IgA nephropathy syndrome

Since Berger's original paper on mesangial IgA-IgG deposition with hematuria, there have been a number of clinical and pathological studies regarding IgA immune complexes, the mechanisms of glomerular IgA deposition leading to glomerular injury and animal models of IgA nephropathy. During the last quarter of this century, glomerular changes such as IgA nephropathy have also been observed in cases associated with other diseases, such as systemic lupus erythematosus, Schoenlein-Henoch purpura, liver cirrhosis and chronic inflammatory diseases of the lung. This evidence supports the idea of an IgA nephropathy syndrome. On the other hand, IgA is thought to be an important humoral factor at the mucosal immune system and appears to have an antibody function against various etiologic candidates of extrinsic or intrinsic substances at the mucosal and systemic immune system. Glomerular IgA deposition in IgA nephropathy syndrome is thought to result from elevated levels of circulating immune complexes or aggregated IgA due to an overproduction of polymeric IgA as antibodies in the serum and due to the clearance impairment of IgA immune complexes in the hepatic and splenic phagocytic system. The glomerular IgA subclass is not one-sided, but should be evaluated in comparison with the age of patients at renal biopsy; this indicates the approximate age of onset. Cirrhotic IgA glomerulonephritis is not related to Hepatitis B or C virus infection, but to the pathophysiologic condition of liver cirrhosis. Various etiologic candidates such as viral, microbial, dietary antigens or auto-antigens have been listed and experimental models of IgA nephropathy syndrome have provided some clues in understanding the etiology of primary IgA nephropathy. However much still remains to be clarified and some specific epitopes common among these etiologic candidates will have to be identified.     

Immunoelectron microscopy of IgA nephropathy

The distribution of IgA, IgG, IgM, C3, and albumin in kidney biopsy specimens from 11 children and adults with recurrent gross and microscopic hematuria and IgA nephropathy and 7 control specimens were evaluated by the direct peroxidase-labeled antibody method and electron microscopy. Granular masses of reaction product (RP), representing IgA, IgG, IgM, and C3, were observed within the mesangial matrix of glomeruli from all patients with IgA nephropathy. Occasional smaller masses of IgA-RP and C3-RP were noted along the peripheral glomerular capillary loops, the tubular basement membranes, and within the interstitial matrix of some patients. Large amounts of IgA-RP and C3-RP were present within the walls of small renal arterioles of several patients. These observations support the concept that immune-complex deposits are involved in the pathogenesis of IgA nephropathy and suggest that vascular deposits may have a more important role in the progression of the disease in some patients.     

Inhibition of neutrophil migration by serum IgA from patients with IgA nephropathy.

Previously we showed that patients with IgA nephropathy present high serum levels of polymeric IgA and that in vitro polyclonal stimulation of their peripheral blood lymphocytes results in the synthesis of a large amount of true polymeric IgA. The aim of this study was to determine if the serum of patients with IgA nephropathy was capable of suppressing the directional migration of human normal polymorphonuclear cells (PMN), as do the polymeric fractions of IgA myeloma. Incubation of controls' PMN with fresh or heat-inactivated patients' plasma impaired the casein-induced directional migration significantly more than incubation with controls' plasma. This inhibitory effect was closely linked to polymeric IgA fractions and to a lesser extent with monomeric IgA immune complexes. The removal of IgA by immunoadsorption from patients' plasma completely abolished the migration suppression observed on controls' PMN. These results suggest that the high serum levels of polymeric IgA observed in patients with IgA nephropathy, by inhibiting directional migration and phagocytosis of PMN, and probably monocytes, could facilitate the persistent circulation and renal deposition of immune complexes.     

IgA nephropathy with subendothelial deposits

Summary IgA nephropathy with subendothelial deposits in the capillary walls of the glomeruli (IgA type 2) was compared histometrically and clinically with IgA nephropathy without subendothelial deposits (IgA type 1) and membranoproliferative glomerulonephritis with subendothelial deposits (MPGN). Study cases consisted of 32 biopsies from 26 patients of IgA type 1, 25 biopsies from 20 patients of IgA type 2 and 31 biopsies from 27 patients of MPGN. Histological changes of the glomeruli consisted of an increase in the mesangial matrix and hypercellularity in the mesangium in both types of IgA nephropathy, and the degree of the changes was a little higher in IgA type 2 than in IgA type 1 (0.02<P<0.05). Mesangial changes of MPGN were marked as compared with IgA type 1 and IgA type 2 (P< 0.001). Histometry of the mesangium on the cases followed up showed that the degree of mesangial thickening increased with lapse of time in IgA type 2 and MPGN, whereas it remained unchanged up to 13 years in IgA type 1. Proteinuria tended to be mild in IgA type 1, moderate in IgA type 2, and marked in MPGN. The impairment of renal function was observed in 21.9% of IgA type 1, in 36.0% of IgA type 2 and in 58.1% of MPGN. IgA type 2 has been shown to be pathologically and clinically intermediate between IgA type 1 and MPGN. These results suggest that there is a clinicopathological overlap between IgA nephropathy and MPGN with IgA deposition.     

A quantitative analysis of the mesangium in children with IgA nephropathy: sequential study

Quantitative analysis of the mesangial matrix and cells was performed on serial renal biopsies from 41 children with IgA nephropathy. In the repeat renal biopsy, nine patients showed a significant increase of mesangial matrix, 29 showed no change and in three there was a significant decrease. Eight of the nine patients (89 per cent) with a matrix increase had persistent proteinuria at the second biopsy, whereas only 14 of the 32 (44 per cent) without a matrix increase had persistent proteinuria (P less than 0.05). Although the mesangial matrix increased in patients with persistent proteinuria, there was no decrease in patients with clinical remission. In contrast to the mesangial matrix, mesangial cells significantly decreased in 23 patients, did not change in 16, and significantly increased in only two in the second biopsy. These findings suggest that mesangial matrix increase is usually an irreversible change and that persistent proteinuria is associated with matrix increase with worsening in glomerular morphology and clinical outcome. This study indicates the importance of serial renal biopsy in children with IgA nephropathy with persistent proteinuria.     

C3, C4, factor B and HLA-DR alpha mRNA expression in renal biopsy specimens from patients with IgA nephropathy.

The deposition of complement in the kidney mesangium is a constant finding associated with renal injury in IgA nephropathy, even though IgA does not bind complement. We have previously reported that complement gene expression in the kidney increases concurrently with the progression of immune complex disease in murine lupus nephritis. We have now studied the expression of C3, C4, factor B and HLA-DR alpha mRNA by in situ hybridization in renal biopsy specimens of patients with IgA nephropathy and compared these findings to those in patients with other immune-mediated diseases of the kidney, hereditary nephritis and normal kidney. In IgA nephropathy, C3 and factor B mRNA were expressed in the renal tubular epithelial cells, while no expression of either C3 or factor B mRNA was apparent in the glomerulus. Specimens from patients with other immune-mediated forms of chronic glomerulonephritis also showed a similar pattern of expression of C3 and factor B mRNA only in the tubules, but not in the glomerules. However, C3 and factor B mRNA were not found in normal kidney tissue or biopsy specimens from patients with hereditary nephritis. C4 mRNA was expressed in the tubular epithelial cells in all specimens examined, indicating that C4 mRNA is constitutively expressed in the human kidney. In IgA nephropathy HLA-DR alpha mRNA was observed in the interstitium, but not the tubules or glomerular cells. In contrast, HLA-DR alpha mRNA was present in the glomerulus and scattered in the interstitium in other immune-mediated kidney diseases. There was no expression of HLA-DR alpha mRNA in hereditary nephritis or normal kidney. Our findings, which reflect the immunopathogenic events in vivo, provide new insights as to the interpretation of the molecular immunology of this immune complex disease.     

Identification and characterization of IgA and Vicia villosa-binding T cell subsets in rheumatoid arthritis.

Autoimmunity may be due to augmentation of immune responses by human CD8 cells which bind the lectin Vicia villosa (VV). We have investigated T cells in rheumatoid arthritis (RA) by double immunofluorescence flow cytometry, in order to assess VV-binding CD8 and CD4 cells from the peripheral blood and synovial fluid. A significant increase in CD8+VV adherent (P less than 0.0001) and CD4+VV adherent cells (P less than 0.001) was found in synovial fluid, as compared with peripheral blood from patients with RA. A significant increase in VV-binding CD8+ or CD4+ cells was, however, not found in the blood of patients with RA, as compared with controls. We suggest that the lack of VV-binding T cells separated from blood, in contrast to those from synovial fluid, may be due to an inhibiting agent expressing N-acetyl D-galactosamine. Indeed, IgA1 is rich in N-acetyl D-galactosamine, it inhibits VV binding to T cells and is significantly bound to CD8 cells (P less than 0.001). The IgA1 was then characterized and in about half the patients J chains and secretory component was found, suggesting that the IgA1 is of the polymeric and secretory variety. IgA bound to the T cells engaged the Fc alpha receptors and a significant decrease in the Fc alpha receptors was found in CD8 cells (P less than 0.0001) and CD4 cells (P less than 0.01). Desorption studies were then carried out on CD8 and CD4 cells which showed that a loss of cell-bound IgA1 was associated with an increase in VV binding. Conversely, adsorption of IgA to T cells was associated with a loss in VV binding. The results suggest that the failure of VV binding to CD8+ and CD4+ cells from peripheral blood of patients with RA can be ascribed to cell-bound IgA1. Cytophilic IgA1 may inhibit the function of CD8+VV binding cells, thereby preventing augmentation of the systemic immune response, consistent with the lack of extra-articular disease in these patients with RA.     

Receptors for IgA on human lymphocytes—I. Detection and specificity

In this study large numbers of peripheral blood lymphocytes bearing receptors specific for IgA (RFcα) were detected by a rosetting technique using highly sensitized ox erythrocytes (EAα). Although significant percentages of RFcα bearing cells could be detected immediately after isolation (30%), even greater percentages of lymphocytes (65%) expressed RFcα after overnight incubation. Detection of RFcα was dependent on the degree of sensitization of the indicator cells by IgA antibody. The percentages of cells bearing receptors for IgA, IgG or IgM, indicated that some lymphocytes (T cells) bearing receptors for IgA also bear Fc receptors for another Ig isotype. Rosette inhibition studies using myeloma immunoglobulins suggested that RFcα have a greater specificity for the IgA2 than for the IgA1 subclass. That monomer blocked IgA rosette formation with approximately the same efficiency per mg as the dimer provided evidence that neither secretory component nor multivalent Fc display were critical to interaction with RFcα. Furthermore, the ability of a myeloma IgA with a missing Cα3 domain to inhibit IgA rosette formation indicated that the site on IgA which interacts with RFcα is in the Cα2 domain and is not dependent on H chain pairing. These findings seem consistent with a major role in secretory immune defense for RFcα and the cells with which they are associated.     

Immunological abnormalities in patient with IgA nephropathy

T cell immunity and phagocytic activity were studied in the blood of patients with IgA nephropathy in order to clarify their roles in the pathogenesis of IgA nephropathy. The percentages of total T lymphocytes, helper T cell and suppressor T cells were significantly reduced in patients. A significantly elevated helper T cell/suppressor T cell ratio in patients showed a predominant reduction in suppressor T cells. There was a significant relationship between histologic findings and helper T cell/suppressor T cell ratio in patients. Natural Killer (NK) cell activity was significantly reduced but the lymphocyte response after phytohemagglutinin (PHA) stimulation was not in patients. ConA-induced suppressor cell activity was not depressed despite of a decrease in suppressor T cells in patients. Phagocytic activity of polymorphonuclear leucocytes (PMNs) ingesting yeasts was significantly reduced in patients. Also an inverse correlation was found between serum IgA levels and phagocytic activity of PMN. It is concluded that suppressor T cell defects, depressed phagocytic activity and impaired NK cell activity may play a role in the pathogenesis of IgA nephropathy.