The biological basis for current treatment strategies for granulomatous disease in common variable immunodeficiency

Abstract

Purpose of review: The pathogenesis of granulomatous disease in common variable immunodeficiency (CVID) is still largely unknown, which hampers effective treatment. This review describes the current knowledge on the pathogenesis of granuloma formation in CVID and the biological basis of the current treatment options.

Recent findings: Histological analysis shows that T and B cells are abundantly present in the granulomas that are less well organized and are frequently associated with lymphoid hyperplasia. Increased presence of activation markers such as soluble IL-2 receptor (sIL-2R) and IFN-ɣ, suggest increased Th1-cell activity. Moreover, B-cell abnormalities are prominent in CVID, with elevated IgM, BAFF, and CD21low B cells correlating with granulomatous disease progression. Innate immune alterations, as M2 macrophages and neutrophil dysregulation, indicate chronic inflammation. Therapeutic regimens include glucocorticoids, DMARDs, and biologicals like rituximab.

Summary: Our review links the biological context of CVID with granulomatous disease or GLILD to currently prescribed therapies and potential targeted treatments.

Box 1

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FIGURE 1

Comprehensive representation of described topics of this review. The left side shows alterations in blood or bronchoalveolar-lavage fluid biomarkers, followed by histologic organization of the granulomatous microenvironment. Targeted and general immunomodulatory therapies for granulomatous lymphocytic interstitial lung disease (GLILD) or granulomatous disease in common variable immunodeficiency are depicted on the right side. The target therapies section highlights the mechanisms of action for T-cell-specific and B-cell-specific treatments represented by cyclosporine, abatacept, sirolimus, and rituximab. Furthermore, the general therapies section indicates the use of disease-modifying antirheumatic drugs (DMARDs; azathioprine, methotrexate, mycophenolate mofetil, anti-TNF-α agents) and glucocorticoids as general immunomodulating therapies affecting a broad cellular spectrum. Image created with BioRender.com.