It is commonly stated that mucosal immunity plays a role in the pathogenesis of IgA nephropathy (IgAN); however, the search for specific eliciting factors has been largely inconclusive. A ...dysregulated mucosal immune system with defective immune tolerance to commonly encountered pathogens or alimentary components is likely to be the key factor in triggering IgAN. Most of the interest, particularly in Asia, was being focussed on the possibility of modulating the mucosal immune system by tonsillectomy, a simple way of eradicating a source of pathogens, meanwhile reducing mucosal-associated immune system (mucosal-associated lymphoid tissue, MALT), but results are still inconclusive. Over the last years, a resurgence of interest has addressed the role of intestinal immunity facing dietary components, like gluten or the complex intestinal flora, the microbiota. The latter is focussing particular interest in recent reports, because it can vary according to diet and environmental factors, is modulated by the host genes and influences, in return, the MALT activity. Some data suggest a tempting new hypothesis for a strong intestine-kidney connection in IgAN. A defective immune tolerance might favour an abnormal response to microbiota with alterations of the intestinal barrier, including increased alimentary antigens and bacterial toxins absorption, triggering MALT activation and subclinical intestinal inflammation. This can produce abnormal response to alimentary antigens or commensal microbes with synthesis of aberrantly glycosylated polymeric IgA1 which eventually enter the circulation with renal deposits formation. The hypothesis is tempting also because it offers new treatment options, targeted to subclinical intestinal inflammation or microbiota modifications.
Current guidelines suggest treatment with corticosteroids (CS) in IgA nephropathy (IgAN) when proteinuria is persistently ≥1 g/d despite 3-6 months of supportive care and when eGFR is >50 ml/min per ...1.73 m(2). Whether the benefits of this treatment extend to patients with an eGFR≤50 ml/min per 1.73 m(2), other levels of proteinuria, or different renal pathologic lesions remains unknown. We retrospectively studied 1147 patients with IgAN from the European Validation Study of the Oxford Classification of IgAN (VALIGA) cohort classified according to the Oxford-MEST classification and medication used, with details of duration but not dosing. Overall, 46% of patients received immunosuppression, of which 98% received CS. Treated individuals presented with greater clinical and pathologic risk factors of progression. They also received more antihypertensive medication, and a greater proportion received renin angiotensin system blockade (RASB) compared with individuals without immunosuppressive therapy. Immunosuppression was associated with a significant reduction in proteinuria, a slower rate of renal function decline, and greater renal survival. Using a propensity score, we matched 184 subjects who received CS and RASB to 184 patients with a similar risk profile of progression who received only RASB. Within this group, CS reduced proteinuria and the rate of renal function decline and increased renal survival. These benefits extended to those with an eGFR≤50 ml/min per 1.73 m(2), and the benefits increased proportionally with the level of proteinuria. Thus, CS reduced the risk of progression regardless of initial eGFR and in direct proportion to the extent of proteinuria in this cohort.
The term 'legacy effect'--a memory of a treatment which produces benefits long after the cessation of the intervention--was adopted for the first time to describe the benefits of early and strict ...control of diabetes on cardiovascular complications. The search for a similar effect for early treatment of immune-mediated renal diseases, interrupting some self-amplification loops of the pathogenetical immunological mechanisms and leaving a permanent memory, is fascinating. Some recent reports suggest a long-term beneficial or legacy effect of early treatment of IgA nephropathy after a randomized controlled trial (RCT) using mycophenolate mofetil, methylprednisolone pulses or steroid/immunosuppressive multiple therapy, or prolonged steroid doses associated with tonsillectomy. Long-lasting effects of treatments are more likely to be achieved in early stages of IgA nephropathy, when mesangial proliferative or endocapillary hypercellular lesions are pre-eminent over sclerosis, and when proteinuria is not massive, above all in young patients. The long-term results considered are relevant, but have the counterpart of the risk of drug toxicity or side effects, which are particularly undesired in patients with a mild disease. Hence, there is interest for drugs targeting the intestinal mucosal immunity with a little systemic effect, aimed at interrupting the initial pathogenetical mechanism. The possibility of modulating anti-inflammatory regulatory T cells by modifying inducible enzymes is another fascinating field of future research.
Aberrant glycosylation in IgA nephropathy (IgAN). Immunoglobulin A nephropathy (IgAN) patients exhibit circulating IgA1 with reduced galactose (Gal) and/or sialic acid (Neu5Ac) and increased exposure ...of N-acetylgalactosamine (GalNAc). These IgA glycoforms fix complement and in mesangial cells regulate integrin expression, enhance nitric oxide synthase (NOS) activity, decrease endothelial growth factor synthesis, meanwhile depressing proliferation and increasing apoptotis. Drugs can be targeted to the effects enhanced by aberrantly glycosylated IgA1 on mesangial cells. Recent data suggest that aberrant IgA1 glycosylation may modulate clinical expression and progression of IgAN.
Summary
Background
Gap‐junctional intercellular communication is crucial for epidermal cellular homeostasis. Inability to establish melanocyte–keratinocyte contact and loss of the intercellular ...junction’s integrity may contribute to melanoma development. Connexins, laminins and desmocollins have been implicated in the control of melanoma growth, where their reduced expression has been reported in metastatic lesions.
Objectives
The aim of this study was to investigate connexin 31·1 (GJB5) expression and identify any association with BRAF mutational status, prognosis of patients with melanoma and mitogen‐activated protein kinase (MAPK) inhibitor (MAPKi) treatment.
Methods
GJB5 expression was measured at RNA and protein level in melanoma clinical samples and established cell lines treated (or not) with BRAF and MEK inhibitors (MEKi), as well as in cell lines which developed MAPKi resistance. Findings were further validated and confirmed by analysis of independent datasets.
Results
Our analysis reveals significant downregulation of GJB5 expression in metastatic melanoma lesions compared with primary ones and in BRAF‐mutated vs. BRAF‐wildtype (BRAFWT) melanomas. Likewise, GJB5 expression is significantly lower in BRAFV600E compared with BRAFWT cell lines and increases on MAPKi treatment. MAPKi‐resistant melanoma cells display a similar expression pattern compared with BRAFWT cells, with increased GJB5 expression associated with morphological changes. Enhancement of BRAFV600E expression in BRAFWT melanoma cells significantly upregulates miR‐335‐5p expression with consequent downregulation of GJB5, one of its targets. Furthermore, overexpression of miR‐335‐5p in two BRAFWT cell lines confirms specific GJB5 protein downregulation. Reverse transcriptase quantitative polymerase chain reaction analysis also revealed upregulation of miR‐335 in BRAFV600E melanoma cells, which is significantly downregulated in cells resistant to MEKi. Our data were further validated using the TCGA_SKCM dataset, where BRAF mutations associate with increased miR‐335 expression and inversely correlate with GJB5 expression. In clinical samples, GJB5 underexpression is also associated with patient overall worse survival, especially at early stages.
Conclusions
We identified a significant association between metastases/BRAF mutation and low GJB5 expression in melanoma. Our results identify a novel mechanism of gap‐junctional protein regulation, suggesting a prognostic role for GJB5 in cutaneous melanoma.
What is already known about this topic?
GJB5 expression has never been studied in melanoma.
Although there is very limited knowledge about connexins in melanoma, these types of gap‐junction proteins have recently been linked with late stages of tumorigenesis and metastasis and are considered as tumour suppressors.
What does this study add?
This study establishes a significant association between BRAFV600E, metastases and GJB5 downregulation in melanoma.
GJB5 underexpression also correlates with worse patient overall survival. Therefore, the data support a prognostic role for GJB5 in cutaneous melanoma.
What is the translational message?
This study highlights the importance of monitoring the integrity of connexin and junctional proteins during melanomagenesis, providing novel therapeutic target options for melanoma treatment, as well as a novel prognostic biomarker to predict melanoma progression.
Linked Comment: J.E. Fromme and P. Zigrino. Br J Dermatol 2022; 186:13–14.
Plain language summary available online
Background:
Factors predictive of renal outcome were investigated in 219 cases of biopsy-proven Henoch-Schönlein purpura nephritis (HSPN); 83 children and 136 adults enrolled in a national study were ...followed up for up to 27 years (median, 4.5 years).
Methods:
The criterion for defining disease progression was time elapsed until doubling of baseline creatinine level and until dialysis therapy. Age, sex, data at onset (renal function, proteinuria, hematuria, hypertension, and crescents), and data during follow-up (proteinuria and therapy) were tested as covariates.
Results:
Multivariate Cox regression analysis indicated the following parameters as independent prognostic predictors: age (adults versus children, relative risk, 3.57; 95% confidence interval, 1.18 to 10.79;
P = 0.024 for creatinine level doubling; relative risk, 14.89; 95% confidence interval, 1.72 to 129.07;
P = 0.014 for dialysis therapy), sex (females versus males, relative risk, 5.71; 95% confidence interval, 1.67 to 19.55;
P = 0.006 for creatinine level doubling; relative risk, 26.03; 95% confidence interval, 2.64 to 256.73;
P = 0.005 for dialysis therapy), and mean proteinuria during follow-up (for each 1 g/d of protein increase, relative risk, 1.77; 95% confidence interval, 1.35 to 2.32;
P < 0.001 for creatinine level doubling; relative risk, 1.73; 95% confidence interval, 1.18 to 2.52;
P = 0.005 for dialysis therapy). Information for mean proteinuria levels during follow-up increased the sensitivity at logistic regression to 62.5%, with dialysis therapy as the end point. No data detected at diagnosis, including renal function impairment, proteinuria, hypertension, and crescentic nephritis (involving >50% of glomeruli in only 2.6%), were significantly related to functional decline at multivariate Cox.
Conclusion:
This analysis indicates that, even more than when decreased renal function, severe proteinuria, hypertension, or crescents are present at onset, the risk for progression of HSPN (greater in adults and females) was associated with increasing mean proteinuria levels during follow-up.
We investigated Toll-like receptors (TLR-3, -4 and -7) expression in circulating mononuclear cells of patients with immunoglobulin A nephropathy (IgAN), a disease with debated relationships with ...mucosal immunity. TLR-4 expression (detected by fluorescence activated cell sorter) and mRNA transcriptional levels (Taqman) were significantly higher in patients with IgAN than in healthy controls (P = 0·00200 and P = 0·0200). TLR-3 and TLR-7 were not modified significantly. In IgAN patients proteinuria was correlated significantly with TLR-4 expression (P = 0·0312). In a group of nephrotic syndromes, TLR-3, -4 and -7 expression was similar to healthy controls. A significant difference in TLR-4 expression and mRNA levels was found between very active IgAN patients (proteinuria > 1 g/1·73 m²/day in association with severe microscopic haematuria) and inactive patients (proteinuria < 0·5 g/1·73 m²/day, with absent or minimal haematuria). No correlation with levels of aberrantly glycosylated IgA1, age, renal biopsy features or therapy was found. This study shows for the first time an up-regulation of TLR-4 in circulating mononuclear cells of patients with IgAN, particularly in association with proteinuria and heavy microscopic haematuria.
Oxidative stress in IgA nephropathy Coppo, R; Camilla, R; Amore, A ...
Nephron. Clinical practice,
10/2010, Letnik:
116, Številka:
3
Journal Article
Recenzirano
IgA nephropathy (IgAN) is characterized by mesangial deposits of IgA1, likely due to accumulation of IgA immune complexes. The activation of intracellular signaling mostly results in oxidative ...stress, as detected in mesangial cells cultured with aberrantly glycosylated IgA or IgA aggregates and in renal biopsies of patients with IgAN. Signs of altered oxidation/antioxidation balance have been detected in sera and/or in erythrocytes of patients with IgAN, including increased levels of lipoperoxide or malondialdehyde and reduced activity of superoxide dismutase, catalase and glutathione peroxidase. Moreover, increased levels of a marker of oxidative stress, advanced oxidation protein products (AOPPs), have been reported to be significantly associated with proteinuria and disease progression in patients with IgAN. AOPPs are often carried by albumin and can in turn enhance the oxidative stress in the circulation. Recent research suggests that the nephrotoxicity of aberrantly glycosylated IgA1 in IgAN is enhanced in the presence of systemic signs of oxidative stress, and it is tempting to hypothesize that the level of the oxidative milieu conditions the different expression and progression of IgAN.
Proteasome (PS) is a sophisticated protein degradation machinery comprising a 20S proteolytic core particle provided with caspase-like, trypsin-like and chymotrypsin-like activities on ...ubiquitinilated proteins. The products of this selective, complex, controlled and strictly coordinated system play a crucial role in cell cycle progression and apoptosis; activation of transcription factors, cytokines and chemokines; degradation and generation of MHC class I-presented peptides. PS has recently emerged as a promising drug target in cancer therapy, and bortezomib has been approved for refractory multiple myeloma. PS proteolysis is crucial for the degradation of the inhibitory protein IkB of nuclear factor kB (NF-kB), and hence, an interesting field of research has been developed on possible benefits of drugs with anti-PS activity in disease conditions with hyper-expression of NF-kB. PS inhibitors are being adopted in pilot studies in antibody-mediated renal rejection and in AL amyloidosis, with increasing scientific interest in possible applications in lupus, IgA nephropathy, idiopathic nephrotic syndrome and renal fibrosis. The most often used PS inhibitor, bortezomib, has a severe peripheral neurotoxicity, and the search for effective and less toxic PS-targeted drugs is a challenging area also in nephrology.
PDF
