Novel immune cross-talk between inflammatory bowel disease and IgA nephropathy

The mechanisms underlying the complex correlation between immunoglobulin A nephropathy (IgAN) and inflammatory bowel disease (IBD) remain unclear. This study aimed to identify the optimal cross-talk genes, potential pathways, and mutual immune-infiltrating microenvironments between IBD and IgAN to elucidate the linkage between patients with IBD and IgAN. The IgAN and IBD datasets were obtained from the Gene Expression Omnibus (GEO). Three algorithms, CIBERSORTx, ssGSEA, and xCell, were used to evaluate the similarities in the infiltrating microenvironment between the two diseases. Weighted gene co-expression network analysis (WGCNA) was implemented in the IBD dataset to identify the major immune infiltration modules, and the Boruta algorithm, RFE algorithm, and LASSO regression were applied to filter the cross-talk genes. Next, multiple machine learning models were applied to confirm the optimal cross-talk genes. Finally, the relevant findings were validated using histology and immunohistochemistry analysis of IBD mice. Immune infiltration analysis showed no significant differences between IBD and IgAN samples in most immune cells. The three algorithms identified 10 diagnostic genes, MAPK3, NFKB1, FDX1, EPHX2, SYNPO, KDF1, METTL7A, RIDA, HSDL2, and RIPK2; FDX1 and NFKB1 were enhanced in the kidney of IBD mice. Kyoto Encyclopedia of Genes and Genomes analysis showed 15 mutual pathways between the two diseases, with lipid metabolism playing a vital role in the cross-talk. Our findings offer insights into the shared immune mechanisms of IgAN and IBD. These common pathways, diagnostic cross-talk genes, and cell-mediated abnormal immunity may inform further experimental studies.</p

Kaplan-Meier curve of cumulative catheter patency.

<p>Patients with TDCs through left IJV (Blue, n = 28) were compared with those through right EJV (purple, n = 21). TDCs, tunneled cuffed dialysis catheters; IJV, internal jugular vein; EJV, external jugular vein.</p

Kaplan-Meier curve of primary catheter patency.

<p>Patients with TDCs through left IJV (Blue, n = 28) were compared with those through right EJV (purple, n = 21). TDCs, tunneled cuffed dialysis catheters; IJV, internal jugular vein; EJV, external jugular vein.</p

Study diagram.

<p>Abbreviations: IJV, internal jugular vein; EJV, external jugular vein; VA, vascular access; TDCs, tunneled cuffed dialysis catheters.</p

Protein contents of IL-6, IL-18, and TTP in urine and serum samples.

<p>Samples from urine (A) and serum (B) of patients from the normal (n = 41), diabetic without proteinuria (n = 33), diabetic with microalbuminuria (n = 29), and diabetic with clinical proteinuria (n = 25) groups were analyzed by ELISA. The data are presented as mean±S.E. *<i>P</i>< 0.05, **<i>P</i> < 0.01 compared with normal healthy controls, ^## P<0.01 compared with diabetic without proteinuria, and ^△△P<0.01 compared with diabetic with microalbuminuria.</p

Characteristics of all subjects.

<p>The data are presented as mean±S.E.</p><p>*<i>P</i> < 0.05</p><p>***<i>P</i> < 0.001 versus normal healthy controls.</p><p>BMI: body mass index; HbA1c: hemoglobin A1c; TG: triglyceride; Cr: creatinine; BUN: blood urea nitrogen; ACR, albumin to creatinine ratio; H-CRP: high-sensitive C-reactive protein. ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin Ⅱ receptor antagonist</p><p>Characteristics of all subjects.</p

mRNA levels of IL-6, IL-18, and TTP in urine and serum samples.

<p>Samples from urine (A and B) and serum (A and C) were analyzed by semi-quantitative RT-PCR and visualized by electrophoresis on acrylamide gels. Representative gels are shown in A; and quantification of the results of patients from each group (normal, n = 41; diabetic without proteinuria, n = 33; diabetic with microalbuminuria, n = 29; and diabetic with clinical proteinuria, n = 25) is shown in B and C. The data are presented as mean±S.E. *<i>P</i> < 0.05, **<i>P</i> < 0.01 compared with normal healthy controls, ^## P<0.01 compared with diabetic without proteinuria, and ^△△P<0.01 compared with diabetic with microalbuminuria.</p

Characteristics of all subjects.

<p>The data are presented as mean±S.E.</p><p>*<i>P</i> < 0.05</p><p>***<i>P</i> < 0.001 versus normal healthy controls.</p><p>BMI: body mass index; HbA1c: hemoglobin A1c; TG: triglyceride; Cr: creatinine; BUN: blood urea nitrogen; ACR, albumin to creatinine ratio; H-CRP: high-sensitive C-reactive protein. ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin Ⅱ receptor antagonist</p><p>Characteristics of all subjects.</p

Inverse relationship between serum TTP and IL-18 or IL-6.

<p>The correlation between serum TTP and IL-6 (A) or IL-18 (B) protein levels was determined by plotting the corresponding values for individual diabetic patients. A best fit line is drawn.</p