Background and Aims

The complement system is a powerful tool of innate immunity to combat pathogens and maintaining host homeostasis. Pathogens activate the classical (CH50) and lectin pathway wherein the alternative pathway (AP) can serve as an “amplification loop”. The AP is also capable of autoactivation, allowing continuous monitoring for pathogens by generating small amounts of C3b. Complement factor I (CFI) plays a crucial role in the negative regulation of C3b, leading to the generation of degradation products such as C3d. Unrestricted localized overactivation of the AP due to a CFI deficiency is mainly associated with renal diseases like atypical hemolytic-uremic syndrome (aHUS) and C3 glomerulopathies (C3G).

Methods

We present two cases illustrating the laboratory hallmarks of a CFI defect.

Results

In both patients CH50, AP50 and serum complement factor C3 was reduced. A quantitative CFI deficiency was found in one patient, whereas the serum level of CFI was normal in the second patient thus initially misdiagnosed as a C3 deficiency. However, based on reduced levels of C3d, targeted sequencing revealed a compound heterozygous mutation in the CFI gene confirming a functional CFI defect. Interestingly, both patients presented with recurrent and invasive pneumococcal infections.

Conclusions

Inherited quantitative and functional deficiencies of regulator CFI can induce overactivation of the alternative pathway and typically results in reduced levels of the degradation product C3d; a diagnostic hallmark for CFI deficiency. In case of general overactivation, CFI deficiency can also present with recurrent pneumococcal infections rather than renal disease due to reduced serum C3, secondary to overconsumption.

Background and Aims

Primary immunodeficiencies and immune dysregulation disorders have an increased susceptibility to develop lymphomas. The vast majority are B cell lymphomas, whereas T cell lymphomas (TCL) are extremely rare and carry a poor prognosis, similar as in the general population. Most cases of TCL were observed in patients with antibody deficiency or combined immunodeficiencies with associated or syndromic features.

Methods

We describe the case of a 46-year-old male patient.

Results

The patient presented in 2017 with recurrent skin abscesses and severe transient neutropenia. In addition, he developed diffuse lymphadenopathies and splenomegaly with reduced serum immunoglobulin levels (IgG and IgM) and peripheral blood analysis showed an atypical monoclonal CD4⁺CD7^-lymphocytosis.

Lymph node biopsy showed atypical paracortical hypertrophy, suggestive of a reactive hyperplasia in the context of an underlying immunodeficiency. Two years later, the patient presented with B symptoms, generalized adenopathy and splenic infarction. Histologic examination of the spleen showed nodular white-pulp hyperplasia with periarteriolar T-zone hyperplasia and granulomas, as was observed in a cohort of CVID patients. A repeat lymph node biopsy revealed progression of the clonal lymphoid hyperplasia to a peripheral PTCL-NOS (peripheral T cell non-Hodgkin lymphoma, not otherwise specified).

Conclusions

Immunodeficiency-associated lymphoid hyperplasia is challenging. Isolated evidence of clonality in biopsy material can precede the diagnosis of lymphoma. Currently, further investigations are ongoing in this patient, to define a genetic cause for the underlying immunodeficiency by analysis for germline-encoded mutations in patient’s fibroblasts and somatic mutational analysis of the tumor sample.