B Cell Receptor Affinity and B Cell Subset Identity Integrate to Define the Effectiveness, Affinity Threshold, and Mechanism of Anergy

Abstract

In this study we show that BCR affinity and subset identity make unique contributions to anergy. Analysis of anti-Smith (Sm) B cells of different affinities indicates that increasing affinity improves anergy’s effectiveness while paradoxically increasing the likelihood of marginal zone (MZ) and B-1 B cell differentiation rather than just follicular (FO) B cell differentiation. Subset identity in turn determines the affinity threshold and mechanism of anergy. Subset-specific affinity thresholds for anergy induction allow discordant regulation of low-affinity anti-Sm FO and MZ B cells and could account for the higher frequency of autoreactive MZ B cells than that of FO B cells in normal mice. The mechanism of anergy changes during differentiation and differs between subsets. This is strikingly illustrated by the observation that blockade of BCR-mediated activation of FO and MZ B cells occurs at different levels in the signaling cascade. Thus, attributes unique to B cells of each subset integrate with signals from the BCR to determine the effectiveness, affinity threshold, and mechanism of anergy.

The regulation of autoreactive B cells during innate immune responses

“…2-12H/Vκ4 B cells are anergic and all subsets are hyporesponsive to LPS in vitro. Additionally, MZ B cells exhibit a block in BCR signaling [70]. LPS-stimulated 2-12H/Vκ4 B cells are repressed by IL-6 and sCD40L (unpublished data).…”

“…The 2-12H/Vκ4 Tg mouse was generated to examine regulation of higher affinity anti-Sm responses [70]. B cells from this mouse are distributed among splenic transitional, FO, and MZ subsets, as well as the peritoneal B-1 subset [70].…”

“…Restricting the light chain that pairs with 2-12H allowed for the analysis of Sm-specific B cells of moderate and low affinity [32,70]. The 2-12H/Vκ4 Tg mouse was generated to examine regulation of higher affinity anti-Sm responses [70].…”

Inflammation, Aging and Cancer: Friend or Foe?

“…These events include simultaneous expression of anti-inflammatory mediators, hormones and growth factors (e.g., NFkB, interleukins, VEGF, FGF, cortisol, etc) enzymes and antioxidants [e.g., catalase, superoxide dismutases (SODs)]. The inflammatory responses induce pain and swelling (e.g., perhaps through binding of histamine-receptornerves within target tissue vasculatures) or tearing that would facilitate destruction and/or dilution of microorganisms and injured cells as well as termination of inflammation and tissue repair and reconstruction (Abraham and John 2010, Akhiani 2005, Bonetti et al, 2003, Boon et al, 2006, Diz et al, 2008, Drayton et al, 2006, Fischetti and Tedesco 2006, Helleboid et al, 1991, Khatami etal, 1984, Khazaie et al, 2011, Serhan and Savill 2005, Smith and Popmihajlov 2008, Soehnlein and Lindbom 2010, Spite and Serhan 2010, Vasto et al, 2007. These interdependent and complex immunobiological cross talks are examples of numerous other sophisticated bilateral communications between immune and non-immune systems that are orchestrated during acute inflammatory responses to maintain and protect the psychophysiological and architectural integrity of organ systems throughout life.…”

“…Communications errors between CMI and HI due to oxidative stress-induced over-, or under expression of immune or non-immune responses, aberrations in chromosomal, genetic and epigenetic components, enzymes, antibodies, receptors/adaptors or surface molecules are implicated in a variety of chronic allergies, neurodegenerative and autoimmune diseases, non-Hodgkin lymphoma, Sjogren's disease, and/or tumorigenesis and cancer (Berosbaken et al, 2009, Booman et al, 2008, Culmsee and Landshamer 2006, D'Amato et al, 2007, Davis et al, 2011, Drayton et al, 2006, Dvorak 1986, Harvey et al, 2008, Kabelitz and Medzhitov 2006. Polarization of Immune Cells: As shown in Table 1, inflammatory mediators with known dual (polarization) properties include toll-like receptors (TLRs 1-9), tumour necrosis factor- and receptor (TNF-/TNFR), MCP-1-CCL2, macrophage colony-stimulating factor (M-CSF), transforming growth factor-(TGF-), granulocyte M-CSF (GM-CSF), histamine, heparin, membrane metaloproteases (MMPs), prostaglandins (e.g., PGF1/PGI-2 to PGE2), cytokine suppressor molecules (e.g., S100 family of calcium-binding proteins), enzymes (e.g., tryptase/chymase, neutrophil-derived serine proteases, indolamine 2, 3-dioxygenase), , Diz et al, 2008, Fischetti and Tedesco 2008, Gordon 2005, Gounaris etal, 2007, Gurish and Boyce 2006, Khatami 2008a, b, Lee et al, 2002, Mackawa and Watanabe 2007, Nishioka et al, 2011, Peerschke et al, 2006, Ribatti et al, 2003, Smith and Popmihajlov 2008, Soehnlein and Lindbom 2010, Suzuki et al, 1998, Thompson et al, 2006, Quezada et al, 2004, Valencia et al, 2011, Wagner 2008 Oxidative stress or continuous exposure to irritants could damage immune surveillance (protection) in either or both immune-responsive and immune-privileged tissues (Figure 3). Oxidative stress could induce exaggerated c...…”