Regional induction of adhesion molecules and chemokine receptors explains disparate homing of human B cells to systemic and mucosal effector sites: dispersion from tonsils

Abstract

Ethical constraints restrict direct tracking of immune-cell migration throughout the human body in vivo. We, therefore, used deletion of the immunoglobulin M (IgM) heavy-chain constant-gene (C) segment as a marker to provide a dispersal signature of an effector B-cell subset (IgD ؉ IgM ؊ CD38 ؉ ) induced selectively in human tonsils. By DNA analysis, the C deletion identified dissemination of such blasts and their plasma-cell progeny to peripheral blood, lymph nodes, and bone marrow, as well as to mucosae and glands of the upper airways. Also the endocervix was often positive, while the small intestine was mainly negative, as could be expected from the identified homingmolecule profile of the marker cells, with relatively low levels of integrin ␣4␤7 and CC chemokine receptor 9 (CCR9). Of further importance for vaccine design, the circulating cells expressed abundantly CD62L (L-selectin) and CCR7, which provided a mechanism for integration of respiratory and systemic immunity. Most mucosal vaccines are at present administered perorally, and our results suggested that the nasal route is no alternative for vaccination against rotavirus or other small-intestinal infections in humans. However, immunization of nasopharynx-associated lymphoid tissue clearly appears preferable to target respiratory pathogens and may to some extent also protect against infections of the female genital tract. IntroductionMost pathogens use mucosae as portals of entry, and mucosal vaccines are therefore desirable, 1 particularly to elicit secretory IgA (SIgA) antibodies. 2,3 The secretory antibody system represents a major first-line defense and is triggered by antigens targeting mucosa-associated lymphoid tissue (MALT), which samples antigens directly from epithelial surfaces. 4 T and B cells activated in MALT home preferentially to mucosal effector sites, where B cells after extravasation undergo terminal differentiation. The local plasma-cell (PC) progeny cooperates with the polymeric Ig receptor (pIgR) to provide SIgA and secretory IgM (SIgM) antibodies. 5,6 Thus, locally produced IgA dimers and IgM pentamers are actively exported by the pIgR. For this epithelial transport mechanism to be operative, the Ig polymers depend on a selective structural incorporation of the J chain, 6,7 although the cytoplasmic expression of this peptide is a common characteristic of mucosal PCs regardless of their concurrent Ig isotype. 8,9 Induction of immunity at various mucosae is clearly an integrated response, but the traditional term "a common mucosal immune system" has detracted from the fact that there may be considerable compartmentalization. 4,5 This has been difficult to substantiate, however, because no inherent marker exists for mucosal B cells that unequivocally identify their MALT origin. Also notably, homing studies performed with primed human T cells, traced by 111 In labeling or gene marking, have provided conflicting results. 10,11 Nevertheless, rational site selection for mucosally applied vaccines would require detailed knowledge of w...

Serum and mucosal antibody responses to pneumococcal protein antigens in children:relationships with carriage status

“…Mucosal B cells from adenoids home preferentially to mucosae and glands of the upper airways [41]. Although the phenotype of the antibody-secreting cells that generated the IgG detected in our cultures was not determined, dual staining of immunocytes for IgG and immunoglobulin J chain showed that some IgG + immunocytes, from adenoids but not from PBMC, co-express J chain (Fig.…”

TLR4-Mediated Sensing of Campylobacter jejuni by Dendritic Cells Is Determined by Sialylation

“…Further studies are required to demonstrate which soluble factors are responsible for the proliferation of B cells by supernatants from C. jejuni-activated DCs and whether B cells show gene rearrangements and maturate into Ab-producing plasma cells in this particular context. In addition, future studies should account for the various enteric and tonsillar B cell subsets, which may differ in the expression of homing receptors (39).…”

Redundant Role of Chemokines CCL25/TECK and CCL28/MEC in IgA+ Plasmablast Recruitment to the Intestinal Lamina Propria After Rotavirus Infection

“…Isolated SI LP, MLN, and SP lymphocytes were stained with different combinations of GFP-VLP and the following anti-mouse Abs (all obtained from BD Pharmingen unless specified): IgA FITC (Southern Biotechnology Associates); B220 PerCP (RA3-6B2); ␣ 4 ␤ 7 PE or allophycocyanin (DATK32.2, allophycocyanin-labeled by Chromoprobe); CCR9 allophycocyanin (242503; R&D Systems); CD138 PE (281-2); and a dump PE or biotin, which included Thy 1.2 (53-2.1), CD-11c (HL3), CD-11b (M1/7), and IgD (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). After staining, cells were washed once and fixed with 1% paraformaldehyde (Electron Microscopy Sciences).…”

“…Because of the variety of tissues in which CCL28 is expressed, it was suggested that the CCL28/CCR10 interaction may function as a unifying mucosal homing mechanism for IgA ϩ plasmablasts/PC (17). However, it has recently been shown that nasal-associated lymphoid tissuederived human B cells, which also express CCR10, have limited access to the SI because they express low levels of CCR9 and ␣ 4 ␤ 7 (18). Hence, the coexpression of homing and chemokine receptors contributes greatly to the compartmentalization of the mucosal immune system, with important implications for the development of effective vaccines (19).…”