ADVANCES IN IMMUNOLOGY

By P. LATAI

CONTENTS 1 THE ROLE OF INNATE IMMUNITY IN B CELL ACQUISITION OF ANTIGEN WITHIN LNS 1 INTRODUCTION 2 FDC ARE A MAJOR RESERVOIR FOR MEMBRANE-BOUND ANTIGEN 3 HOW DO ANTIGENS ARRIVE AT FDC? 4 ROLE OF LN RESIDENT DC IN TRANSPORT OF ANTIGEN ACKNOWLEDGMENTS REFERENCES 2 NUCLEAR RECEPTORS, INFLAMMATION, AND NEURODEGENERATIVE DISEASES 2 NUCLEAR RECEPTORS: FAMILY MEMBERS AND MOLECULAR FUNCTIONS 3 IMMUNE CELLS IN THE CNS—MICROGLIA, ASTROCYTES, AND LYMPHOCYTES 4 IN?AMMATORY COMPONENTS OF NEURODEGENERATIVE DISEASES 5 SUMMARY AND PERSPECTIVES ACKNOWLEDGMENT 3 NOVEL TOOLS FOR MODULATING IMMUNE RESPONSES IN THE HOST— POLYSACCHARIDES FROM THE CAPSULE OF COMMENSAL BACTERIA 1 INTRODUCTION: THE INTESTINAL MICRO?ORA 2 THE POLYSACCHARIDE CAPSULE AND BACTERIAL COLONIZATION OF THE HOST 3 PROFESSIONAL APCS IN GUT-ASSOCIATED LYMPHOID TISSUE AND SHAPING OF MUCOSAL IMMUNITY BY COMMENSAL MICROBES 4 INTESTINAL IN?AMMATION AND IMMUNOREGULATION 5 POLYSACCHARIDE A FROM B FRAGILIS 6 CONCLUSION 4 THE ROLE OF MECHANISTIC FACTORS IN PROMOTING CHROMOSOMAL TRANSLOCATIONS FOUND IN LYMPHOID AND OTHER CANCERS 1 CHROMOSOMAL TRANSLOCATIONS IN CANCER 2 DNA RECOMBINATION IN B AND T CELL DEVELOPMENT 3 MECHANISTIC FACTORS THAT IN?UENCE THE APPEARANCE OF CHROMOSOMAL TRANSLOCATIONS 4 PERSPECTIVE CHAPTER THE ROLE OF INNATE IMMUNITY IN B CELL ACQUISITION OF ANTIGEN WITHIN LNS 1 INTRODUCTION 2 FDC ARE A MAJOR RESERVOIR FOR MEMBRANE- BOUND ANTIGEN 2 1 B CELL SYNAPSE 2 2 FDC RETAIN ANTIGEN VIA COMPLEMENT AND FC RECEPTORS 2 3 B CELLS ACQUIRE ANTIGEN FROM FDC 3 1 SUBCAPSULAR MACROPHAGES AS GUARDIANS OF LYMPHATICS 3 2 TYPE OF ANTIGEN DICTATES PATHWAY FOR TRANSPORT ABSTRACT OVER THE PAST DECADE, IT HAS BECOME APPARENT THAT B CELLS ACQUIRE ANTIGENS PRIMARILY FROM MEMBRANE SURFACES AND THAT UPTAKE IS AN ACTIVE PROCESS INVOLVING A SYNAPSE BETWEEN THE B CELL RECEPTOR, ADVANCES IN IMMUNOLOGY VOLUME EXPRESSION BY COGNATE B CELLS IS IMPORTANT IN ANTIGEN UPTAKE FROM FDC AS DISCUSSED IN MORE DETAIL BELOW, SUZUKI ET AL , 2009 REPORTED THAT B CELL EXPRESSION OF CD21/35 WAS IMPORTANT IN DIRECT ACQUISITION OF ANTIGEN IN VIVO FOR MODERATE AFFINITY (KD ¼ 1 10 7) ANTIGENS BUT WAS LESS IMPOR- TANT FOR ANTIGENS AT VERY HIGH AFFINITY (KD ¼ 1 1010) THUS, IN A PHYSIO- LOGICAL SETTING IN WHICH ANTIGENS ARE MOST LIKELY BOUND TO A MEMBRANE AND COUPLED WITH C3D LIGAND, THE CORECEPTOR IS IMPORTANT IN ENHANCEMENT OF BCR SIGNALING 2 2 FDC RETAIN ANTIGEN VIA COMPLEMENT AND FC RECEPTORS EARLY HISTOLOGICAL STUDIES REPORTED ACCUMULATION OF LABELED ANTIGEN– ANTIBODY IMMUNE COMPLEXES (ICS) WITHIN THE SPLENIC AND LYMPH NODE TISSUES (MILLER AND NOSSAL, 1964; PAPAMICHAIL ET AL , 1975) CHARACTERIZA- TION OF THE CELLS BEARING ANTIGEN DEPOSITS BY ELECTRON MICROSCOPY IDENTI- FIED DENDRITIC SHAPED CELLS REFERRED TO AS FDC (MANDEL ET AL , 1980; TEW ET AL , 1990) FDC ARE STROMAL CELLS IN ORIGIN AND THEIR DIFFERENTIATION WITHIN THE LYMPHOID AND SPLENIC FOLLICLES IS DEPENDENT ON LYMPHOTOXIN ALPHA AND BETA (LTA,B) (FU ET AL , 1997; KONI ET AL , 1997) ANTIGENS (COATED WITH C3D) ARE MOST EFFICIENTLY TAKEN-UP ON FDC BY COMPLEMENT RECEPTORS ADVANCES IN IMMUNOLOGY VOLUME (KATAKAI ET AL , 2008; ROOZENDAAL ET AL , 2009) IN SUMMARY, FDC ARE NOT ONLY ESSENTIAL FOR MAINTAINING THE B CELL FOLLICLES BUT ALSO SERVE AS A MAJOR RESERVOIR FOR ANTIGEN THAT IS CAPTURED PREDOMINANTLY VIA COMPLEMENT RECEPTORS MICE DEFICIENT IN CD21/35 OR WHICH FAIL TO FORM NORMAL FDC HAVE IMPAIRED GC AND FAIL TO DEVELOP IGG MEMORY B CELLS RESPONSES TO BOTH PARTICULATE AND SOLUBLE ANTIGENS 2 3 B CELLS ACQUIRE ANTIGEN FROM FDC FDC PROVIDE AN EFFICIENT SURFACE FOR B CELL UPTAKE OF MEMBRANE-BOUND ANTIGEN AND INDUCTION OF SIGNALING VIA THE CD21/CD19 CORECEPTOR AS THE CELL SURFACE IS DECORATED WITH ANTIGEN COUPLED TO C3D MOREOVER, THE EXTEN- SIVE DENDRITIC-LIKE NETWORK FORMED BY FDC PROVIDES A LARGE SURFACE VOLUME FOR DISPLAY OF ANTIGEN-C3D (ALLEN AND CYSTER, 2008; EL SHIKH ET AL , 2007) (FIG 1 1C) AS DISCUSSED IN MORE DETAIL BELOW, THE FDC AND MRC (KATAKAI ET AL , 2008) ARE MAJOR SOURCES OF THE B CELL CHEMOKINE CXCL-13; THEREFORE, B CELLS ARE ATTRACTED TO THE NETWORK AND APPEAR TO TRAFFIC ALONG THE FDC AND RETICULAR FIBERS (BAJENOFF ET AL , 2006) STUDIES IN VITRO SUPPORT THE INCREASE IN EFFICIENT BCR STIMULATION WHEN ANTIGEN IS PRESENTED VIA FDC COMPARED TO SOLUBLE FORM (QIN ET AL , 1998) WHETHER FDC ARE THE ONLY SOURCE OF ANTIGEN IS CONTROVERSIAL PRETREAT- MENT OF PRIMATES WITH A DECOY RECEPTOR, THAT IS, LT BR IG-FUSION PROTEIN, TRANSIENTLY DEPLETES FDC AND LOSS OF THE FRC RETICULAR NETWORK WITHIN THE B CELL AREA BUT DOES NOT IMPAIR THE PRIMARY IGM RESPONSE TO A HAPTENATED ANTIGEN (GOMMERMAN ET AL , 2002) HOWEVER, FDC NETWORKS OR CLUSTERS ARE REQUIRED FOR FORMATION OF GC AND EFFICIENT SWITCHING TO IGG (FU ET AL , 1997; KOSCO AND GRAY, 1992) USING A TG B CELL MODEL IN WHICH IG SECRETION IS BLOCKED, SHLOMCHIK AND COLLEAGUES FOUND THAT DEPOSITION OF IG IMMUNE COMPEXES (ICS) ON FDC WAS NOT REQUIRED FOR HUMORAL IMMUNITY TO A SOLUBLE ANTIGEN (HABERMAN AND SHLOMCHIK, 2003) THUS, GC FORMATION AND DEVELOPMENT OF MEMORY B CELLS APPEARED TO BE NORMAL IN THE ABSENCE OF FORMATION OF ICS BY IG INTERESTINGLY, THEY OBSERVED THAT COMPLEMENT C3 WAS ACTIVATED DIRECTLY ON THE SURFACE OF THE COGNATE B CELL IN THE ABSENCE OF SECRETED IG (ROSSBACHER AND SHLOMCHIK, 2003) MOREOVER, ADVANCES IN IMMUNOLOGY VOLUME C3D (BLUE) (C) SCHEMATIC REPRESENTATION OF B CELL AND FDC ACQUISITION OF ANTIGENS 1 POLY- CLONAL B CELLS CAN CAPTURE AND TRANSPORT C3D-COATED ANTIGEN VIA CD21/35 RECEPTORS ON THE CELL SURFACE THE C3D-COATED ANTIGENS CAN THEN BE TRANSFERRED TO CD21/35 ON THE SURFACE OF FDC 2 A SECOND MECHANISM IS THAT FDC CAN TRAP ANTIBODY–ANTIGEN COMPLEXES ON THEIR SURFACE VIA FCRIIB ADVANCES IN IMMUNOLOGY VOLUME