CD27, a member of the TNFR superfamily, is used to identify human memory B cells. Nonetheless, CD27(+) B cells are present in patients with HIGM1 syndrome who are unable to generate GCs or memory B cells. CD27(+)IgD(+) fetal B cells are present in umbilical cord blood, and CD27 may also be a marker of the human B1-like B cells. To define the origin of naïve CD27(+)IgD(+) human B cells, we studied B cell development in both fetal and adult tissues. In human FL, most CD19(+) cells coexpressed CD10, a marker of human developing B cells. Some CD19(+)CD10(+) B cells expressed CD27, and these fetal CD27(+) cells were present in the pro-B, pre-B, and immature/transitional B cell compartments. Lower frequencies of phenotypically identical cells were also identified in adult BM. CD27(+) pro-B, pre-B, and immature/transitional B cells expressed recombination activating gene-1, terminal deoxynucleotidyl transferase and Vpre-B mRNA comparably to their CD27(-) counterparts. CD27(+) and CD27(-) developing B cells showed similar Ig heavy chain gene usage with low levels of mutations, suggesting that CD27(+) developing B cells are distinct from mutated memory B cells. Despite these similarities, CD27(+) developing B cells differed from CD27(-) developing B cells by their increased expression of LIN28B, a transcription factor associated with the fetal lymphoid lineages of mice. Furthermore, CD27(+) pro-B cells efficiently generated IgM(+)IgD(+) immature/transitional B cells in vitro. Our observations suggest that CD27 expression during B cell development identifies a physiologic state or lineage for human B cell development distinct from the memory B cell compartment.

Background Severe Combined Immunodeficiency (SCID) is a syndrome uniformly fatal during infancy unless recognized and treated successfully by bone marrow transplantation or gene therapy. Because SCID infants have no abnormal physical appearance, diagnosis is usually delayed unless newborn screening is performed. Objective In this study, we sought to evaluate the presenting features of all 172 SCID patients transplanted at this institution over the past 31 years. Methods We reviewed original charts from 172 consecutive classic SCID patients who received either T cell-depleted HLA-haploidentical (N=154) or HLA-identical (N=18) non-ablative related marrow transplants at Duke University Medical Center from 1982–2013. Results The mean age at presentation was 4.87 months. When there was a family history of early infant death or known SCID (63/172 or 37%), the mean presentation age was much earlier, 2.0 months compared to 6.6 months. Failure to thrive was common, with 84 patients (50%) having a weight less than the 5th percentile. The leading infections included oral moniliasis (43%), viral infections (61/172 35.5%) and Pneumocystis jiroveci (26%) pneumonia. The group mean ALC was 1454/cmm; 88% of the infants had an ALC less than 3000/cmm. Absent thymic shadow was seen in 92% of infants with electronic radiographic data available. An absence of T cell function was found in all patients. Conclusions SCID infants appear normal at birth but later present with failure to thrive and/or recurrent fungal, viral and bacterial infections. Low ALCs and absent thymic shadow on chest x-ray are key diagnostic clues. The absence of T cell function confirms the diagnosis.

AAAAI Position Statements,Work Group Reports, and Systematic Reviews are not to be considered to reflect current AAAAI standards or policy after five years from the date of publication. The statement below is not to be construed as dictating an exclusive course of action nor is it intended to replace the medical judgment of healthcare professionals. The unique circumstances of individual patients and environments are to be taken into account in any diagnosis and treatment plan. The statement reflects clinical and scientific advances as of the date of publication and is subject to change.

Expression of activation-induced cytidine deaminase (AID) by germinal center (GC) B cells drives the processes of immunoglobulin (Ig) somatic hypermutation (SHM) and class switch recombination (CSR) necessary for the generation of high affinity IgG serum antibody and the memory B-cell compartment. Increasing evidence indicates that AID is also expressed at low levels in developing B cells but to date, this early, developmentally regulated AID expression has no known function. Does the timing and extent of AID expression in developmentally immature, non-GC B cells provide clues to reveal its physiologic role?Keywords Activation-induced cytidine deaminase Á B-cell development Á Class switch recombination deficiency Á Somatic hypermutation Á Germinal center In 1998, a slim volume of Current Topics in Microbiology and Immunology [1] was introduced by the following statement:Discovery of the mechanism for V(D)J hypermutation remains a basic goal of immunology despite the best efforts of many laboratories. The existence of catalyzed, site-specific mutation and … the somatic evolution of lymphocytes are remarkable adaptations, yet since the discovery of hypermutation in 1970 [2], much hard work has generated little.This cri de coeur was soon answered. In 1999, Tasuku Honjo and his colleagues at Kyoto University identified an enzyme, activation-induced cytidine deaminase (AID), that was preferentially expressed in germinal center (GC) B cells and necessary for Ig class switch recombination (CSR); in the subsequent year, Honjo's group showed that AID was also

Wegener granulomatosis (WG) is an uncommon, idiopathic disorder that is characterized by granulomatous inflammation of the upper and lower respiratory tract, disseminated vasculitis involving small and medium-sized vessels, and focal segmental glomerulonephritis. Approximately 25% to 50% of patients have nervous system involvement. The brain is less frequently involved. We report a case of a 74 year-old previously well woman who presented with rapidly progressing WG that culminated in subarachnoid hemorrhage. Only six cases of subarachnoid hemorrhage in the setting of WG have previously been reported. We review the common presenting signs and symptoms, diagnosis, treatment, and complications of WG.

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CD27 is an accepted marker for memory B cells in humans. However, CD27 expression was recently demonstrated on substantial populations of human B cells in cord blood and fetal liver (FL), tissues that contain few if any memory B lymphocytes. In addition, CD27 expression was recently proposed to identify natural B cells, the human counterpart of murine B-1 B cells. These observations led us to explore the characteristics of human, CD27+ B cells, and particularly developing B cells. Comparing B cells from FL, cord blood, and adult bone marrow (BM), we found CD27 expression as early as the pro-B cell stage. Moreover, the frequency of CD27+ pro-B cells was higher in FL than in BM. Expression of TdT, RAG1 and VpreB in CD27+ pro-B cells was similar to conventional, CD27- pro-B cells, confirming their identity as B-lineage progenitors. Developmentally immature CD27- and CD27+ B cells showed no significant differences in VH gene usage, VH mutation frequencies, or CDRH3 length, excluding the possibility of contamination by memory B cells. Interestingly, when placed in an in vitro culture system optimized to support the maturation of human fetal pro-B cells and murine B-1 B cells, CD27+ pro-B cells differentiated into IgM+ immature and transitional B cells significantly more efficiently than did autochthonous CD27- pro-B cells. In conclusion, we have demonstrated functional CD27+ pro-B cells in FL and BM that may identify a predominantly fetal, B-cell lineage in humans.

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