Taketoshi Yoshida

Memory B and memory plasma cells

Summary:  Vaccination provides a powerful means to control infections. It exploits and exemplifies the ability of the immune system to preserve the information that a specific pathogen has been encountered in the past. The cells and molecular mechanisms of immunological memory are still being discussed controversially. Here, we review the current concepts of memory B cells, the signals involved in their maintenance, and their role in enhanced secondary reactions. Memory plasma cells, secreting protective antibodies over lifetime, have been recognized only recently. Their characterization as cells resting in terms of proliferation and migration, and surviving in dedicated stromal niches, in the absence of antigen, has generated new concepts of how memory cells in general are organized by stroma cells, the ‘resting memory’. In autoimmunity and chronic inflammation, memory B cells and memory plasma cells can be essential players, and they require special attention, as they do not respond to most conventional therapies. Their selective targeting will depend on a molecular understanding of their lifestyle.

Blood-borne human plasma cells in steady state are derived from mucosal immune responses

Providing humoral immunity, antibody-secreting plasma cells and their immediate precursors, the plasmablasts, are generated in systemic and mucosal immune reactions. Despite their key role in maintaining immunity and immunopathology, little is known about their homeostasis. Here we show that plasmablasts and plasma cells are always detectable in human blood at low frequency in any unimmunized donor. In this steady state, 80% of plasmablasts and plasma cells express immunoglobulin A (IgA). Expression of a functional mucosal chemokine receptor, C-C motif receptor 10 (CCR10) and the adhesion molecule beta(7) integrin suggests that these cells come from mucosal immune reactions and can return to mucosal tissue. These blood-borne, CCR10(+) plasmablasts also are attracted by CXCL12. Approximately 40% of plasma cells in human bone marrow are IgA(+), nonmigratory, and express beta(7) integrin and CCR10, suggesting a substantial contribution of mucosal plasma cells to bone marrow resident, long-lived plasma cells. Six to 8 days after parenteral tetanus/diphtheria vaccination, intracellular IgG(+) cells appear in blood, both CD62L(+), beta(7) integrin(-), dividing, vaccine-specific, migratory plasmablasts and nondividing, nonmigratory, CD62L(-) plasma cells of different specificities. Systemic vaccination does not impact on peripheral IgA(+) plasmablast numbers, indicating that mucosal and systemic humoral immune responses are regulated independent of each other.

Adaptation of humoral memory.

Summary:  Immunological memory, as provided by antibodies, depends on the continued presence of antibody‐secreting cells, such as long‐lived plasma cells of the bone marrow. Survival niches for these memory plasma cells are limited in number. In an established immune system, acquisition of new plasma cells, generated in response to recent pathogenic challenges, requires elimination of old memory plasma cells. Here, we review the adaptation of plasma cell memory to new pathogens. This adaptation is dependent upon the influx of plasmablasts, generated in a secondary systemic immune reaction, into the pool of memory plasma cells, the efficiency of competition of new plasmablasts with old plasma cells, and the frequency of infection with novel pathogens. To maintain old plasma cells at frequencies high enough to provide protection and to accommodate as many specificities as possible, an optimal influx rate per infection exists. This optimal rate is approximately three times higher than the minimal number of plasma cells providing protection. Influx rates of plasmablasts generated by vaccination approximately match this optimum level. Furthermore, the observed stability of serum concentrations of vaccine‐specific antibodies implies that the influxing plasmablasts mobilize a similar number of plasma cells and that competitive infectious challenges are not more frequent than once per month.

Bone marrow of NZB/W mice is the major site for plasma cells resistant to dexamethasone and cyclophosphamide: implications for the treatment of autoimmunity.

Antibodies contribute to the pathogenesis of many chronic inflammatory diseases, including autoimmune disorders and allergies. They are secreted by proliferating plasmablasts, short-lived plasma cells and non-proliferating, long-lived memory plasma cells. Memory plasma cells refractory to immunosuppression are critical for the maintenance of both protective and pathogenic antibody titers. Here, we studied the response of plasma cells in spleen, bone marrow and inflamed kidneys of lupus-prone NZB/W mice to high-dose dexamethasone and/or cyclophosphamide. BrdU+, dividing plasmablasts and short-lived plasma cells in the spleen were depleted while BrdU- memory plasma cells survived. In contrast, all bone marrow plasma cells including anti-DNA secreting cells were refractory to both drugs. Unlike bone marrow and spleen, which showed a predominance of IgM-secreting plasma cells, inflamed kidneys mainly accommodated IgG-secreting plasma cells, including anti-DNA secreting cells, some of which survived the treatments. These results indicate that the bone marrow is the major site of memory plasma cells resistant to treatment with glucocorticoids and anti-proliferative drugs, and that inflamed tissues and secondary lymphoid organs can contribute to the autoreactive plasma cell memory. Therefore, new strategies targeting autoreactive plasma cell memory should be considered. This could be the key to finding a curative approach to the treatment of chronic inflammatory autoantibody-mediated diseases.

The improvement of hypoxia correlates with neuroanatomic and developmental outcomes: Comparison of midterm outcomes in infants with transposition of the great arteries or single-ventricle physiology

OBJECTIVES We performed a prospective longitudinal study of the neuroanatomic and developmental changes in infants with transposition of the great arteries (TGA) or single-ventricle (SV) physiology to identify variables in anatomic development of the brain associated with functional impairment. METHODS Thirty-three infants with congenital heart defects, 23 with SV and 10 with TGA, were studied at around 1 year old (time 1) and 3 years old (time 2) by magnetic resonance imaging of the brain. Neurodevelomental assessment was performed at the same time. RESULTS The whole and frontal lobe volumes were significantly reduced in both groups at time 1 compared with normal control subjects (P < .01). However, by time 2 whole and frontal brain volumes were normal in the TGA group but remained significantly smaller (P < .01) in the SV group. In agreement with these findings, the mental development index (MDI) was lower (P < .05) at time 1 in both groups but improved to normal levels at time 2 in the TGA group. In the SV group, both MDI and the psychomotor development index (PDI) were significantly decreased at both time 1 and time 2 (P < .01). These patients continued to experience hypoxia, and multivariate analysis revealed that functional oxygen saturation was significantly associated with PDI. Further, the PDI score correlated with whole and regional brain volumes (P < .05). CONCLUSIONS Neuroanatomic and developmental outcomes improve progressively in infants with TGA, unlike those with SV physiology. Impaired cerebral circulation and hypoxia may have significant effects on brain growth and development in infants with critical congenital heart disease.

Gonadal mosaicism of a TAZ (G4.5) mutation in a Japanese family with Barth syndrome and left ventricular noncompaction

TAZ (G4.5) was initially identified as the gene associated with Barth syndrome and left ventricular noncompaction (LVNC). The purpose of this study was to investigate patients with LVNC for disease-causing mutations in TAZ. In 124 Japanese patients, including 50 families, mutation analysis of TAZ was performed using DNA sequencing. A splice donor mutation was identified in two brothers with Barth syndrome and LVNC, and a sister who was asymptomatic. However, the variant was not identified in either parent or the maternal grandparents, all of whom were asymptomatic. Due to the recurrent inheritance of this variant by each of the children we concluded that this was evidence of gonadal mosaicism in the obligate carrier mother, the first reported occurrence of this in Barth syndrome.

Phenotypic Analysis of B-Cells and Plasma Cells

B-cells and antibody-secreting plasma cells are key players in protective immunity, but also in autoimmune disease. To understand their various functions in the initiation and maintenance of autoimmune pathology, a detailed dissection of their functional diversity is mandatory. This requires a detailed phenotypic classification of the diversity of B-cells. Here, technologies of immunocytometry and ELISpot are described in detail, and their value for phenotypic characterization of cells of the B lineage, as well as for preparative cell sorting, to further characterize them functionally and on the molecular level are described.

Type I interferon as a biomarker in autoimmunity and viral infection: a leukocyte subset-specific analysis unveils hidden diagnostic options

Interferon alpha and its surrogates, including IP-10 and SIGLEC1, paralleled changes of disease activity in systemic lupus erythematosus (SLE). However, the whole blood interferon signature (WBIFNS)—the current standard for type I IFN assessment in SLE—does not correlate with SLE disease activity in individual patients over time. The underlying causes for this apparent contradiction have not been convincingly demonstrated. Using a multicenter dataset of gene expression data from leukocyte subsets in SLE, we identify distinctive subset-specific contributions to the WBIFNS. In a subsequent analysis, the effects of type I interferon on cellular blood composition in patients with SLE and hepatitis B were also studied over time. We found that type I interferon mediates significant alterations in whole blood composition, including a neutropenia and relative lymphocytosis. Given different effects of type 1 interferon on different leukocyte subsets, these shifts confound measurement of a type 1 interferon signature in whole blood. To minimize and overcome these limitations of the WBIFNS, we suggest to measure IFN-induced transcripts or proteins in a specific leukocyte subset to improve clinical impact of interferon biomarkers.Key messagesMyeloid cells contribute more to the WBIFNS in SLE than their lymphocytic counterpart.Very similar leukocyte subsets reveal distinctive IFN signatures.IFN alpha mixes up composition of blood and leads to a preferential neutropenia, yielding relative lymphocytosis.

Increased production of intestinal immunoglobulins in Syntenin-1-deficient mice.

Syntenin-1 is an intracellular PDZ protein that binds multiple proteins and regulates protein trafficking, cancer metastasis, exosome production, synaptic formation, and IL-5 signaling. However, the functions of Syntenin-1 have not yet been clearly characterized in detail, especially in vivo. In this study, we generated a Syntenin-1 knock out (KO) mouse strain and analyzed the role(s) of Syntenin-1 in IL-5 signaling, because the direct interaction of Syntenin-1 with the cytoplasmic domain of the IL-5 receptor α subunit and the regulation of IL-5 signaling by Syntenin-1 have been reported. Unexpectedly, the number of IL-5-responding cells was normal and the levels of fecal immunoglobulins were rather higher in the Syntenin-1 KO mice. We also found that IgA and IgM production of splenic B cells stimulated in vitro was increased in Syntenin-1 KO mice. In addition, we showed that a distribution of intestinal microbial flora was influenced in Syntenin-1 KO mice. Our data indicate that Syntenin-1 negatively regulates the intestinal immunoglobulin production and has a function to maintain the intestinal homeostasis in vivo. The analysis of Syntenin-1 KO mice may provide novel information on not only mucosal immunity but also other functions of Syntenin-1 such as cancer metastasis and neural development.

Successful treatment of hemochromatosis with renal tubular dysgenesis in a preterm infant

We report the first surviving case of neonatal hemochromatosis with renal tubular dysgenesis. Renal failure was treated with peritoneal dialysis. Although hepatic failure from neonatal hemochromatosis was progressive, repeated exchange transfusions improved jaundice and coagulopathy. The patient gained weight and received a liver transplantation from her father.