Interleukin-12 (IL-12) is a cytokine that promotes cell-mediated immunity to intracellular pathogens by inducing type 1 helper T cell (TH1) responses and interferon-gamma (IFN-gamma) production. IL-12 binds to high-affinity beta1/beta2 heterodimeric IL-12 receptor (IL-12R) complexes on T cell and natural killer cells. Three unrelated individuals with severe, idiopathic mycobacterial and Salmonella infections were found to lack IL-12Rbeta1 chain expression. Their cells were deficient in IL-12R signaling and IFN-gamma production, and their remaining T cell responses were independent of endogenous IL-12. IL-12Rbeta1 sequence analysis revealed genetic mutations that resulted in premature stop codons in the extracellular domain. The lack of IL-12Rbeta1 expression results in a human immunodeficiency and shows the essential role of IL-12 in resistance to infections due to intracellular bacteria.

Thin glomerular basement membrane (GBM) nephropathy, also called familial benign hematuria, is characterized by chronic hematuria and uniform thinning of the lamina densa of the glomerular basement membrane. It generally holds an excellent renal prognosis. Alport syndrome in early stages can also show attenuation of the GBM; conversely, renal insufficiency has been reported in familial benign hematuria. To discern early Alport syndrome from thin GBM nephropathy, we carried out a prospective epidemiological study in which 19 normotensive and non-azotemic adult patients with chronic microscopic (18 of 19) and macroscopic (1 of 19) hematuria and biopsy-proven thin GBM nephropathy were followed for a median of 12 years (range 9 to 15 years). Renal biopsies of thin GBM patients at entry showed an increased incidence of focal global glomerulosclerosis when compared to disease controls as IgA nephropathy (P = 0.047) and normal renal tissue (P = 0.0075). All renal biopsies showed the presence of the Goodpasture antigen when tested immunohistochemically. Presence of Alport syndrome was excluded clinically as none of the patients had complaints of hearing loss or abnormalities by audiography and ophthalmology. At the end of follow-up, the incidence of hypertension in thin GBM nephropathy (35%) exceeded that of healthy clinical controls (P = 0.048), and one hypertensive patient developed mild renal failure. In the normotensive patients, the glomerular filtration rate at follow-up as measured by inulin clearance was reduced in three out of seven; these were over 50 years of age. Although no family members were known to have renal disease at inclusion, within four families six elderly first degree relatives had developed unexplained renal insufficiency at the end of follow-up. Thus, thin GBM nephropathy predisposes to premature glomerular obsolescence, leading in time to increased incidences of hypertension and late onset renal insufficiency.

Thin-basement-membrane nephropathy, also called benign recurrent hematuria, is characterized by diffuse thinning of the glomerular basement membrane and by hematuria. To determine the incidence of thin-basement-membrane nephropathy among patients with idiopathic hematuria, we conducted a prospective study in the nephrology units of three large hospitals in the Netherlands. Eighty normotensive adults without azotemia underwent renal biopsy because of recurrent macroscopic hematuria (n = 26) or persistent microscopic hematuria (n = 54). Idiopathic IgA nephropathy was found in 27 of the 80 patients. Light microscopical examination showed that 42 patients had normal renal tissue. The remaining 11 patients had mesangioproliferative glomerulonephritis (n = 5), interstitial nephritis (n = 3), or focal global glomerulosclerosis (n = 3). Tissue from the 42 patients whose renal biopsy specimens were normal when examined with light microscopy was analyzed morphometrically with electron microscopy to determine the thickness of the glomerular basement membrane. Two subsets of patients were identified by this analysis. In 18, thin-basement-membrane nephropathy was found (mean basement-membrane thickness [+/- SE], 191 +/- 28 nm; normal, 350 +/- 43 nm); all but one of these 18 patients had microscopic hematuria, which persisted during follow-up (median duration, 50 months). (Of the 54 patients who presented with microscopic hematuria, 17 [31 percent] had thin-basement-membrane nephropathy.) The thickness of the glomerular basement membrane was normal in the other 24 patients (361 +/- 69 nm); during follow-up, hematuria disappeared in all 13 of these patients who had macroscopic hematuria, and hematuria resolved in 5 of the 11 patients who had microscopic hematuria. We conclude that in patients with persistent microscopic hematuria, the incidence of thin-basement-membrane nephropathy is similar to that of idiopathic IgA nephropathy. Morphometric analysis of the thickness of the glomerular basement membrane should be included in the workup of adults with persistent microscopic hematuria that is not of urologic origin.

These results support the notion that TBMN is a disease of genetic heterogeneity; it is not a benign renal condition in a substantial number of patients, particularly those in late middle age.

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