BENTA

BENTA is the acronym for "B-cell expansion with NF-kappaB and T-cell anergy".

The primary hallmark of BENTA disease is polyclonal B-cell lymphocytosis in early childhood associated with splenomegaly and lymphadenopathy. Pediatric patients have an excessive accumulation of immature transitional (CD10+CD24hiCD38hi) and mature naïve (IgM+IgD+) polyclonal B cells, with very low proportions of circulating memory and class-switching B cells.

The number of circulating naïve and transitional B cells usually decreases until adulthood, which is probably due to reduced production of immature B cells in the bone marrow.

Conversely, the number of T cells in patients is usually normal in the absence of chronic viral infection (e.g. EBV).

Histologic analysis of the lymphoid tissue shows follicular hyperplasia with an impressive expansion of naïve ^IgD+ B cells in the mantle zones, but a normal number and distribution of ^CD3+ T cells.

It is caused by gain-of-function mutations (GOF mutations) of the CARD11 gene.

The following symptoms are indicative of BENTA disease:

Characteristics of primary immunodeficiency(PID).

Infections: All BENTA patients suffer from frequent ear and sinus infections in childhood, and opportunistic viral infections such as molluscum contagiosum and JC/BK viruses have been identified in some patients. Chronic EBV infection with moderate viremia is also found in about 50% of BENTA patients.

Impaired humoral immune response: Most BENTA patients show a poor humoral immune response to T-cell-independent vaccines such as pneumococcal and meningococcal polysaccharide vaccines, even after repeated booster vaccinations. Some patients also do not develop lasting protective titers against T-cell-dependent conjugate vaccines against pneumococcus (i.e. Prevnar), varicella-zoster virus (VZV) or measles.

Low IgM and IgA levels in serum are inconsistently detectable, with IgG levels varying. In vitro studies on B cells from naïve patients showed impaired differentiation of B cells into plasmablasts and long-lived plasma cells, which is consistent with poor IgG secretion in culture (Arjunaraja S et al. 2017). This could be due to failed induction of specific factors required for plasma cell differentiation, including BLIMP-1 and XBP-1. Conversely, ectopic expression of GOF-CARD11 variants in activated B cells in mice promotes transient expansion of self-reactive plasmablasts and autoantibody production.

T cells from BENTA patients are generally hyporesponsive in culture, with poor proliferation and reduced IL-2 secretion. Although autoantibodies are detected in some patients, autoimmune disease symptoms are not common in BENTA patients, possibly due to underlying defects in B and T cell differentiation.

Germline GOF-CARD11 mutations (p.Cys49Tyr, p.Gly123Ser, p.Gly123Asp, p.Phe130Ile, p.Glu134Gly) can be detected in most BENTA patients. These also occur as somatic GOF mutations of CARD11 in diffuse large B-cell lymphoma (DLBCL) and other lymphoid malignancies (Chan W et al. 2013).

Moreover, ectopic expression of BENTA-associated CARD11 mutants in B and T cell lines leads to spontaneous formation of large protein aggregates, including CARD11, BCL10, MALT1 and phosphorylated IKKα/β, inducing constitutive NF-κB signaling independent of antigen receptor binding.

It can be hypothesized that intrinsic B cell defects in BENTA disease most likely contribute to impaired humoral immunity and frequent infections with extracellular bacteria, while slightly anergic T cells might make BENTA patients more susceptible to certain viral infections.

Patients with splenomegaly, selective B-cell lymphocytosis and frequent sinopulmonary infections at a young age should be suspected of having BENTA disease. Sequencing of CARD11 can reveal variants, especially in the LATCH or CC domains.

It is recommended that BENTA patients be treated clinically with supportive therapy, with minimal therapeutic interventions available. Polyclonal B-cell lymphocytosis in BENTA disease may predispose patients to B-cell malignancies later in life.

However, the efficacy of B-cell-depleting agents in BENTA should be evaluated on a case-by-case basis and may not be necessary as B-cell lymphocytosis resolves over time. A few patients have also received intravenous or subcutaneous immunoglobulin therapy in childhood for infection control. Interestingly, MALT1 protease inhibitors that specifically inhibit CBM signaling without completely blocking NF-κB activation may represent an attractive targeted treatment option for certain BENTA patients These inhibitors are currently being investigated for the treatment of B-cell lymphomas and autoimmune diseases.

1. Arjunaraja S et al. (2017) Intrinsic plasma cell differentiation defects in B cell expansion with NF-kappaB and T Cell anergy patient B cells. Front Immunol 8:913.
2. Chan W et al. (2013) A quantitative signaling screen identifies CARD11 mutations in the CARD and LATCH domains that induce Bcl10 ubiquitination and human lymphoma cell survival. Mol Cell Biol 33:429-443.
3. Dadi H et al. (2018) Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11). J Allergy Clin Immunol 141:1818-1830 e2.