MCH + X. Complex formation and antibody induction

Molecular Pergamon

Immunoloyy, Vol. 28, No. 415, pp. 561-563, Press plc. Printed in Great Britain.

1991

BOOK REVIEWS

MCH +X. Complex Formation Edited by Pavol Ivanyi. Springer, pp. DM 165.

and Antibody Induction. Berlin. 1988, 247 + XXII

induced in C3H mice (H-2’) by L cells (H-2k) transfected with human /I2 microglobulin genes were analyzed by immunoprecipitation and absorption. The results clearly demonstrate anti-H-2P antibodies that cannot be absorbed by L cells alone or by /I2 microglobulin-transfected L cells. The induction of anti-MHC antibodies with soecificitv for H-2Kk associated with bovine &rn was further shown by Schmidt, who immunized AKR recipients with AKR leukemic cells, and by Cramer et al. who produced a monoclonal antibody (COB6-3) by immunization of a Balb/c mouse with syngeneic Con A blasts. This antibody that reacts with H-2Db and with a monomorphic determinant of human HLA class I defines a cross-reacting antigenie determination shared by most HLA class I and certain H-2 antigens bound to bovine &rn. Thus, modified syngeneic cells may induce either classical alloreactive antibodies or antibodies to a neodeterminant (MHC +&m) that cross reacts with various MHC haplotypes. Whether molecular mimicry or additional mechanisms are involved is still an open question. Antibodies induced against MHC-antigen complexes are widely discussed by Ivanyi and Kievits, who raise two questions: (a) Do MHC restricted antibodies exist? and (b) Would the specificity of these antibodies overlap with specificities of T cell receptors? The conclusion drawn by these two authors (in two separate papers) is that there is no evidence for the existence of MHC restricted antibodies. On the other hand, Tamminen and Barber, using Db and influenza nucleoprotein-transfected L cells, produced certain hybridomas-that seem to have a certain-specificity for the Db/NP comnlex. although their soecificitv is broader than that of equhalent cytotixic T cells and their frequency is very low. Similarly, Governy ef al. found similar but not identical patterns between HLA-A2 restricted H-Y antigen specificity CTL and the serum of a certain female patient, whose lymphocytes demonstrated such HLA-A2 restricted H-Y specific activity. A similar unresolved problem was brought up by Van Leeuwen et al. who analyzed thoroughly antisera to “modifying factor” in patients with ankylosing spondylitis (AS). These authors tested the possibility that a rabbit antiserum produced against lymphocytes from AS patients is specified for HLA-B27 associated with a specific AS factor (peptide?), as originally observed by Geczy et al. Using various methods and with various rabbit antisera, original observations with serum produced in Sydney, Australia were reproduced; however, similar sera could not be produced in Europe. An original approach to the question of antibody and CTL recognition of MHC class I antigens is brought by Abastado et al., who constructed, by an original method, hybrid MHC molecules between Kd and Dd antigens, transfected these into L cells, and studied recognition patterns with 59 monoclonal antibodies and 8 CTL clones. Their data clearly demonstrates that CTL recognition is both peptideand MHC-dependent, whereas antibody recognition is mainly dependent on exon structure. The question “What does the T cell receptor recognize?” was also approached in the study by Sette et al., who analyzed the combination of IAd restricted chicken ovalbumin peptide 323-339 variants in induction of IL-2 secretion form two Ova 223-339 specific T cell hybridomas. A six amino acid core (327-332) was found to be critical for binding to IAd, in this core two residues are strongly involved in IAd binding

The mechanisms underlying T cell recognition of foreign antigen in the context of MHC have perplexed the scientific community in the last decade. Recent advances have shed some light on the enigma of MCH + X. First, it was demonstrated that class I and II restricted T cells recognize peptides derived from cellular processing of protein antigens. Secondly, it was discovered that class II molecules bind antigenic peptides in ritro with specificity that correlates with the patterns of MHC restriction, and thirdly, the HLA-A2 crystal structure was solved and a clear peptide binding site was found. These advances have allowed a simple picture to emerge. However, many phenomena remain unexplained. The proceedings of the 1987 Ommen/ Amsterdam meeting published as MHC + X, Complex Formation and Antibody Induction, address many of the MHC-related subjects. A large proportion of the papers address various aspects of MHC-specific antibodies and naturally occurring MHCspecific antibodies. Alloreactive CTL induced by virus injection and various aspects of /I,-microglobulin binding to class I heavy chains are discussed, as are some nonimmunological functions of MHC antigens. Four presentations discuss the natural occurrence of anti-MHC antibodies. Ivanvi et al. describe H-2 soecific antibodies in 25% of aged C57BL (H-2b) mice and less in younger mice. These natural antibodies are mostly of the IgM isotype and are mostly directed against H-2 public specificities, although autoreactive antibodies are rarely found. Gunther similarly describes anti-MHC alloantibodies in 20% of rats, with rare cases of alloreactivity to self. The frequency of such antibodies is strain-dependent and seems to be controlled by both MHC and non-MHC genes. Tongio et al. and Ameglio et al. screened human sera for anti-HLA class I and II antibodies. While the former group found IgM antibodies in about 1% of normal individuals, the latter group observed that antibodies to class I and II MHC antigens-exist in about 80% of sera from drug addicts and hvdalidosis natients. but not in healthv individuals. HIV positiies, HBsAg positives nor in patients infected by various parasites. The mechanisms involved in induction of natural anti-MHC immunity are unknown; hypotheses put forward so far include mimicry by environmental antigens, modified self or polyclonal stimulation. An even more pronounced effect is the induction of H-2 specific antibodies by various modified cells in syngeneic recipients: Pla er al. describe anti-H-2 reactivity patterns induced in C3H x C57BL/F,. (H-2k x H-2”) by L cells (H-2k) after transfection with H-2K” genes, with AKV murine leukemia virus genes or with a combination of these genes. L cells alone or Kb transfectants did not induce alloantibodies. Double transfectants induced antibodies with wide specificities against a number of haplotypes, including autoreactive (anti-H-2b, anti-H-2k or both) antibodies, while virus transfected cells induced antibodies with narrow specificities, including autoreactive antibodies. A second study from the same group (Opolski et al.) showed production of alloreactive and autorective H-2 antibodies by EL4 tumor cells in syngeneic C57BL and an augmentation of antibody production after modification of EL4 cells with Sendai virus. In a third study from this group (Rocca ef al.) alloantibodies 561

562

Book Reviews

and two others are loosely implicated. Nine out of 1 I residues are implicated in TCR binding; of these 3 are overlapping with residues that bind I-Ad. A model of a 2-dimensional planar conformation for the peptide is suggested from these results. Models for MHC-restricted T cell recognition of a synthetic H-2Ld peptide are described by Song et al., who offer two possible models for allorecognition of MHC molecules. In one model, allogenic recognition is described in terms of recognition of a processed peptide restricted by self-MHC, while in the second model, the allo MHC interacts as an alternative self-MHC domain with an unknown peptide, to form a 3-dimensional structure that mimics MHC + X. A number of studies were devoted to various aspects of association of /?rrn with class I heavy chains. Baas et a/. show that in HLA-B27K transgenic mice, the transgene is not expressed in association with murine Bzrn, but is expressed when these mice are crossed with transgenic mice carrying the gene for human &m. Oudshoorn-Snack et al. show that Qal I is a pure T cell marker that is controlled by genes in the Qa-2 region and Tla region and is expressed only in association with &m allele. Myers et al. demonstrate the existence of two Ld forms on the cell surface of an Ld transfectant or Balb/c splenocytes. One form is jI,m-associated and the other is a free form. Thus, cell surface expression of class I heavy chains alone is possible. On the other hand, Peraknav et al. demonstrate that in a series of HLA-A3, HLA-B7 and HLA-CW3 transfected P815 cells, co-transfection with human &rn genes elevates dramatically cell surface expression of the transfected genes. Thus, a species-specific Brn is necessary for stable expression of some class I heavy chains.

Barber studied free and &m-associated H-2K” molecules and his conclusion is that the association with /&rn is mandatory for transport of heavy chain to the cell surface. However, dissociation may occur at later stages, so free heavy chain is found on the cell surface. A fascinating aspect of binding of free &m to cytomegalovirus is described by Grundy et al. They demonstrate that CMV virions bind p2rn to the viral envelope, a process that protects virions from neutralization by anti-CMV antibody, the coated virions also use class I HLA heavy chains as receptors for cellular binding and invasion. The last two reports describe the possible interactions between class I MHC and other cell surface receptors. Claas et ai. describe a set of experiments suggesting that gamma type endorphin (DTy E) receptors are associated with certain MHC cl&s I molecules and that internalization of DRE involves MHC class I. Phiflips et al. corroborates earl&r observations of an association between MHC class I and insulin receptors by demonstrating co-precip~~tion of insulin receptors (IR) with anti-class I antibodies, co-capping of IR-MHC on cells and reduced binding of insulin to MHC negative cell lines. In summary, many of these new studies on the involvement of MHC molecules in immunological and nonimmunological functions better our understanding of these complex molecules.

The Third Component of Complement: Chemistry and Biology. Edited by JOHN D. LAMBRIS. Current Topics in Microbiobgy and Immunology, Vol. 153. Springer, Heidelberg, 1990.

receptors types 1, 2 and 3, decay accelerating factor, membrane cofactor protein and Factor H. Several C3 binding substances found recently on the surface of pathogenic organisms such as viruses, fungi and parasites are described in the following paper. The reader is then presented with updated information on the structure and function of C3a, a C3 peptide with anaphylactic activity, and on the C3a receptors, Recent progress in the analysis of the molecular structure of C3 and the complement proteins interacting with it is next presented. The last two papers of the book discuss the biological and pathological consequences of a genetic C3 deficiency in man and animals (guinea-pigs and dogs) and further describe the analysis of functional epitopes of C3 using monoclonal antibodies. Retrospectively, it appears that the paper on C3 deliciences should have followed the paper on biosynthesis and genetics of C3, the paper on molecular modeling of C3 should have been adjacent to that on the thioester bond of C3 and the last paper should have been adjacent to or included in the third paper (by the same group of authors) on the molecular aspects of C3 interactions with its ligands. Of the four facets of C3, i.e. its genetics. chemistry, biology and pathophysiology, the first three are very well covered, whereas the latter is only touched upon. The nomenclature in the book may sometimes be confusing as different authors call the same complement component by different names. A few examples: C3n,,, (p. 4) appears also as C3(H,O) (p. 79), C3u (p.‘219) an.diC3 (p. 15); Bb (p. 141) is also called Bbi CP. 13): iC3b (P. 48) is also named C3bi (p. 141); Factor D (p. 10) is calledD (p. 13); and CoVF (p. 8) is also abbreviated CVF (p. 23 I). This problem might have been resolved by the editor. Despite that, this is a valuable book and every immunological library and complementologist should have it.

As stated by J. D. Lambris and H. J. Muller-Eberhard in the preface to the book, “The third component of complement, C3, is one of the most versatile proteins and an important participant in immune surveillance and immune response pathways. Its multifunctionality is based on its ability to interact specifically with multiple serum complement proteins, cell surface receptors, and membrane associated reguIatory proteins.” Thirteen well-written and clearly illustrated papers are assembled in this book to provide the reader with a comprehensive overview of the genetics, chemistry and biology of C3, the pivotal protein of the complement system. Each chapter is written by an expert on that subject, thus ensuring reliable and accurate description of the state-of-the-art of the topic presented. Most importantly, through the C3 molecule, the reader is introduced to the multiplicity of the molecular organization and functions of the complement system. The book opens with a brief introduction to the complement system and description of the complement proteins which interact with C3 and its fragments C3b, iC3b and C3d, g. Special emphasis is given to the complement components Factor B, Factor D and properdin and to the C3jCS convertases. C3 biosynthesis and gene structure are then discussed in detail, followed by a structural/functional analysis of human C3 and, most interestingly, of C3 of other animal species, e.g. mouse, rabbit, quail, chicken, xenopus, rainbow trout and lamprey. The following paper describes the thioester bond in C3 (found also in C4 and a2macroglobulin), which enables C3b to form a covalent bond with complement activators. The next four chapters provide an extensive description of six proteins which interact with physiological degradation products of C3, i.e. complement

The Weizmunn rnstifMie of Science.

LEA EISENBACH

Rehocot. Israel

Department of Chemical Immunology, The Weizmann Institute of Science, Rehovot, Israel

ZVI FISHELSON