Combined Immunodeficiency With Late-Onset Progressive Hypogammaglobulinemia and Normal B Cell Count in a Patient With RAG2 Deficiency.

Proteins expressed by recombination activating genes 1 and 2 (RAG1/2) are essential in the process of V(D)J recombination that leads to generation of the T and B cell repertoires. Clinical and immunological phenotypes of patients with RAG deficiencies correlate well to the degree of impaired RAG activity and this has been expanding to variants of combined immunodeficiency (CID) or even milder antibody deficiency syndromes. Pathogenic variants that severely impair recombinase activity of RAG1/2 determine a severe combined immunodeficiency (SCID) phenotype, whereas hypomorphic variants result in leaky (partial) SCID and other immunodeficiencies. We report a patient with novel pathogenic compound heterozygous RAG2 variants that result in a CID phenotype with two distinctive characteristics: late-onset progressive hypogammaglobulinemia and highly elevated B cell count. In addition, the patient had early onset of infections, T cell lymphopenia and expansion of lymphocytes after exposure to herpes family viruses. This case highlights the importance of considering pathogenic RAG variants among patients with preserved B cell count and CID phenotype.

A novel RAG1 mutation reveals a critical in vivo role for HMGB1/2 during V(D)J recombination.

The Recombination Activating Genes, RAG1 and RAG2, are essential for V(D)J recombination and adaptive immunity. Mutations in these genes often cause immunodeficiency, the severity of which reflects the importance of the altered residue or residues during recombination. Here, we describe a novel RAG1 mutation that causes immunodeficiency in an unexpected way: The mutated protein severely disrupts binding of the accessory protein, HMGB1. Although HMGB1 enhances RAG cutting in vitro, its role in vivo was controversial. We show here that reduced HMGB1 binding by the mutant protein dramatically reduces RAG cutting in vitro and almost completely eliminates recombination in vivo. The RAG1 mutation, R401W, places a bulky tryptophan opposite the binding site for HMG Box A at both 12- and 23-spacer recombination signal sequences, disrupting stable binding of HMGB1. Replacement of R401W with leucine and then lysine progressively restores HMGB1 binding, correlating with increased RAG cutting and recombination in vivo. We show further that knockdown of HMGB1 significantly reduces recombination by wild-type RAG1, whereas its re-addition restores recombination with wild-type, but not the mutant, RAG1 protein. Together, these data provide compelling evidence that HMGB1 plays a critical role during V(D)J recombination in vivo.

Hydromorphone neuroexcitation.

Continuous parenteral hydromorphone is used to treat pain in palliative care. Case reports have suggested that neuroexcitatory symptoms, such as agitation, myoclonic activity, and even seizures may occur during administration. However, little information exists on the incidence of these side effects or their relationship to the dose or duration of parenteral hydromorphone. A retrospective chart review was performed on 48 terminally ill hospice patients who received continuous parenteral hydromorphone for pain control. Chart reviews were conducted searching for three neuroexcitatory symptoms: agitation, myoclonus, and seizures; the incidence and relationship of these symptoms were statistically compared to the maximal dose and number of days on continuous parenteral hydromorphone. We found that agitation, myoclonus, and seizures were not associated with the patients gender, age, or diagnosis but found that agitation was associated (p < 0.01) in patients with known metastatic disease. Agitation, myoclonus, and seizures were independently associated with the maximal dose (p < 0.05, p < 0.001, and p < 0.05) and with the duration (p < 0.01, p < 0.05, and p < 0.01) of continuous parenteral hydromorphone A possible mechanism for these findings is hydromorphone-3-glucoronide, a metabolic product of hydromorphone, which has been implicated in neuroexcitatory symptoms in laboratory investigations.