Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity.

The molecular basis of the incomplete penetrance of monogenic disorders is unclear. We describe here eight related individuals with autosomal recessive TIRAP deficiency. Life-threatening staphylococcal disease occurred during childhood in the proband, but not in the other seven homozygotes. Responses to all Toll-like receptor 1/2 (TLR1/2), TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes of all TIRAP-deficient individuals. However, the whole-blood response to the TLR2/6 agonist staphylococcal lipoteichoic acid (LTA) was abolished only in the index case individual, the only family member lacking LTA-specific antibodies (Abs). This defective response was reversed in the patient, but not in interleukin-1 receptor-associated kinase 4 (IRAK-4)-deficient individuals, by anti-LTA monoclonal antibody (mAb). Anti-LTA mAb also rescued the macrophage response in mice lacking TIRAP, but not TLR2 or MyD88. Thus, acquired anti-LTA Abs rescue TLR2-dependent immunity to staphylococcal LTA in individuals with inherited TIRAP deficiency, accounting for incomplete penetrance. Combined TIRAP and anti-LTA Ab deficiencies underlie staphylococcal disease in this patient.

Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.

Human inborn errors of IFN-γ immunity underlie mycobacterial diseases. We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A. This gene encodes a transmembrane protease that degrades the N-terminal fragment (NTF) of CD74 (HLA invariant chain) in antigen-presenting cells. The CD74 NTF therefore accumulates in the HLA class II+ myeloid and lymphoid cells of SPPL2a-deficient patients. This toxic fragment selectively depletes IL-12- and IL-23-producing CD1c+ conventional dendritic cells (cDC2s) and their circulating progenitors. Moreover, SPPL2a-deficient memory TH1* cells selectively fail to produce IFN-γ when stimulated with mycobacterial antigens in vitro. Finally, Sppl2a-/- mice lack cDC2s, have CD4+ T cells that produce small amounts of IFN-γ after BCG infection, and are highly susceptible to infection with BCG or Mycobacterium tuberculosis. These findings suggest that inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of cDC2s and impairing IFN-γ production by mycobacterium-specific memory TH1* cells.

Image-guided brachytherapy for pediatric bladder and/or prostate rhabdomyosarcoma: toward an increased personalization of treatment.: Brachytherapy in uro-pediatric rhabdomyosarcoma.

INTRODUCTION: Rhabdomyosarcoma (RMS) is the most common soft tissue cancer in children. Around 15% of RMS involve the bladder and/or prostate (BP). Overall survival is around 85%. After chemotherapy, patients receive local treatment based on surgery and/or radiotherapy. In recent decades, image guidance and pulsed dose-rate (PDR) brachytherapy have made it possible to personalize treatment, reduce radiation-related toxicity, while maintaining a good tumor control. We report one of the largest series of image-guided brachytherapy for pediatric RMS BP. MATERIAL AND METHODS: The clinical and dosimetric parameters of children treated with brachytherapy for BP RMS between July 2014 and September 2020 were retrospectively reviewed. Patients were treated with a multimodal conservative approach, combining partial conservative surgery (preservation of the bladder neck and urethra), followed by an interstitial brachytherapy procedure. Iridium-192 PDR treatment was administered on the basis of CT and MRI planning. Toxicities were reported according to version 4.0 of the Common Terminology Criteria for Adverse Events. RESULTS: A total of 75 patients were identified, with a median age of 29 months (range 2-84) at diagnosis. The median brachytherapy dose was 60.06 Gy (143 pulses, 0.42 Gy/pulse). With a median follow-up of 44.1 months (range 0.7-90), the 5-year OS and PFS rates were 97.3% and 92% respectively. Median D50% for the bladder and D1cc for the rectum were 38.6 Gy and 49 Gy respectively. The 5-year probability of survival without severe late urinary toxicity (grade 3 or higher) was estimated at 78.8% (CI95%: 68.1-91.1). A total of 9.3% of children experienced grade 2 or 3 late rectal toxicity. CONCLUSIONS: Image-guided PDR brachytherapy offers a personalized treatment for pediatric BP RMS, with a favorable therapeutic index. No prognostic factors for urinary toxicity have been identified. Multicenter studies with larger numbers of patients are needed to clarify these data.