Indian Journal of Pathology and Microbiology

: 2009  |  Volume : 52  |  Issue : 3  |  Page : 458--459

Invasive cryptococcus infections in immunocompetent individuals may suggest defects in CD40/CD40L signaling pathway

Sujoy Khan 
 Path Links Immunology, Scunthorpe General Hospital, Scunthorpe, England, DN15 7BH, United Kingdom

Correspondence Address:
Sujoy Khan
Path Links Immunology, Scunthorpe General Hospital, Scunthorpe, England, DN15 7BH
United Kingdom

How to cite this article:
Khan S. Invasive cryptococcus infections in immunocompetent individuals may suggest defects in CD40/CD40L signaling pathway.Indian J Pathol Microbiol 2009;52:458-459

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Khan S. Invasive cryptococcus infections in immunocompetent individuals may suggest defects in CD40/CD40L signaling pathway. Indian J Pathol Microbiol [serial online] 2009 [cited 2021 Sep 21 ];52:458-459
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I read with interest the case report by Juhi Taneja and colleagues [1] on disseminated cryptococcosis in an immunocompetent adult. The authors comment on the absence of polyclonal hypergammaglobulinemia but do not provide levels of individual immunoglobulin serotypes (IgG, IgA and IgM), as an isolated elevated IgM could be a pointer towards hyper-IgM syndrome. New primary immunodeficiency diseases are being increasingly recognized, particularly when infectious organisms take advantage of a single defective signaling pathway in otherwise immunocompetent individuals. [2]

Immunodeficiency with hyper-IgM (HIGM) may have normal IgM levels but levels of IgG, IgA and IgE are usually low. IgM levels can be variable among affected members of the same family (therefore obtaining a family history is crucial), and an X-linked pattern of similar infections would strongly suggest HIGM-Type 1. Although sophisticated diagnostic facilities are required to establish the diagnosis, features of low IgG ( a universal finding), neutropenia, lymphadenopathy, splenomegaly and serious infections with cytomegalovirus or adenovirus are useful pointers towards the possibility of HIGM. [3]

HIGM-Type 1 affects males due to CD40-ligand (CD40L, CD154) deficiency on activated T cells ( CD40L gene located at Xq26-27), required for B-cell immunoglobulin class switch from IgM. CD40L is a Type II transmembrane protein that binds to CD40 on antigen presenting cells (such as B cells or macrophages). CD40L defect affects monocyte-macrophage activation increasing risk of infection with organisms such as Cryptococcus, [2],[4] Pneumocystis and Histoplasma . Patients may present with IgM+ lymphomas, interstitial pneumonia, chronic diarrhea and ascending cholangitis due to Cryptosporidium parvum , oral ulcers and hepatitis. [3] Failure to detect CD40L on optimally activated T cells clinches the diagnosis of HIGM-Type 1, but as CD40L expression is affected by various factors [age (neonates do not optimally express CD40L), point mutations in CD154 permit expression of non-functional protein], genetic confirmation remains the gold standard. [3],[5]

Although most reports of HIGM-Type 1 are in children, a recent report of toxoplasmosis in an immunocompetent individual with a hypomorphic mutation in the CD40L gene [5] highlights the fact that primary immunodeficiency disorders are not limited to children. Knowledge of the various presentations of these rare primary immunodeficiency syndromes guides testing for these conditions, and correct diagnosis allows specific treatment and genetic counseling.


1Taneja J, Bhargava A, Loomba P, Dogra V, Thakur A, Mishra B. Cryptococcal granulomas in an immunocompromised HIV-negative patient. Indian J Pathol Microbiol 2008;51:553-5.
2Pietrella D, Lupo P, Perito S, Mosci P, Bistoni F, Vecchiarelli A. Disruption of CD40/CD40L interaction influences the course of Cryptococcus neoformans infection. FEMS Immunol Med Microbiol 2004;40:63-70.
3Jo EK, Kim HS, Lee MY, Iseki M, Lee JH, Song CH, et al . X-linked hyper- IgM syndrome associated with Cryptosporidium parvum and Cryptococcus neoformans infections: t0 he first case with molecular diagnosis in Korea. J Korean Med Sci 2002;17:116-20.
4Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, et al . The X-linked hyper-IgM syndrome: c0 linical and immunologic features of 79 patients. Medicine (Baltimore) 2003;82:373-84.
5Yong PF, Post FA, Gilmour KC, Grosse-Kreul D, King A, Easterbrook P, et al . Cerebral toxoplasmosis in a middle-aged man as first presentation of primary immunodeficiency due to a hypomorphic mutation in the CD40 ligand gene. J Clin Pathol 2008;61:1220-2.