Abstract
Primary antibody deficiencies present clinically as reduced or absent plasma antibodies without another identified disorder that could explain the low immunoglobulin levels. Bone marrow-liver-thymus (BLT) humanized mice also exhibit primary antibody deficiency or hypogammaglobulinemia. Comprehensive characterization of B cell development and differentiation in BLT mice revealed other key parallels with primary immunodeficiency patients. We found that B cell ontogeny was normal in the bone marrow of BLT mice but observed an absence of switched memory B cells in the periphery. PC-KLH immunizations led to the presence of switched memory B cells in immunized BLT mice although plasma cells producing PC- or KLH- specific IgG were not detected in tissues. Overall, we have identified the following parallels between the humoral immune systems of primary antibody deficiency patients and those in BLT mice that make this in vivo model a robust and translational experimental platform for gaining a greater understanding of this heterogeneous array of humoral immunodeficiency disorders in humans: (i) hypogammaglobulinemia; (ii) normal B cell ontogeny in bone marrow; and (iii) poor antigen-specific IgG response to immunization. Furthermore, the development of strategies to overcome these humoral immune aberrations in BLT mice may in turn provide insights into the pathogenesis of some primary antibody deficiency patients which could lead to novel clinical interventions for improved humoral immune function.
Highlights
Primary antibody deficiencies are characterized by reduced or absent plasma antibody levels when no other disorder can be identified as causing the immunoglobulin deficits [1,2]
To gain insights into the tissue source(s) of the antibodies present in Bone marrow-liver-thymus (BLT) mouse plasma, we used ELISPOT analyses to quantitate the numbers of IgM, IgA and IgG producing plasma cells generating human antibodies in bone marrow (BM), spleen, lymph nodes (LN), liver and lungs
Primary antibody deficiency is associated with reduced serum IgG and IgA, often accompanied by reduced serum IgM [12]. These disorders, which include common variable immunodeficiency (CVID), result from a spectrum of B cell abnormalities caused by various genetic defects which may affect T, B and potentially other cells [3,4,5,8,9,10,11]
Summary
Primary antibody deficiencies are characterized by reduced or absent plasma antibody levels when no other disorder can be identified as causing the immunoglobulin deficits [1,2]. Given the deficient humoral immune responses in humanized mice, despite their otherwise remarkable recapitulation of the human immune system’s development and function, we examined the potential for BLT mice to serve as a primary antibody deficiency model. To do this we compared the human B cell development, differentiation and function we observed in BLT mice to literature detailing primary antibody deficiency in patients
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