Rheumatic Diseases: Immunological Mechanisms And Prospects For New Therapies

(1999) Edited by J. S. Hill Gaston, Cambridge Press. 288 pages

Reviewed for BloodLine by

Sulaiman George Gegbe
Department of Clinical Haematology
West Suffolk Cambridge Postgraduate Teaching Hospital Trust
Kingston, U.K.

The authors further discussed (chapter 2) T cell immunity and how HLA subtypes and their genetic codes are linked to specific examples of rheumatic diseases such as RA & IDDM. The role of MHC in Autoimmunity (chapter 3) was then explored, with the authors indulging into the complex association of HLA gene cluster of chromosome 6p21.3 (classes I, II & III) and their relative risk contribution to autoimmunity through MHC. The relative Location and function of TNF-a, TNF-b, HSP-70, Al, B8, Cw7, C4A, 21OH, TAPs, LMPs regions on HLA was well documented in the text. The structure of HLA and trimolecular complex was used to explain the relationship between both HLAI & HLAII heterodimer (8-b, 2-a) peptide binding site in relationship to their crystallography and in association with epidemiology. The Function of class MHC I and II in Processing of antigen in endoplasmic reticulum and the function of CLIPS and TAPS was made clear and the Comparison of MHC I and MHCII based on TCR functional and structural CD4 &CD8 molecules was properly elaborated on.

The hunt for therapy was extended to using epidemiological data to established the relative risk relationship between HLA found in Inflammatory Bowel Disease, Ankylosing Spondylytis, Psoriatic Arthritis, Rheumatoid Arthritis, Systemic lupus, Sjogen syndrome, periarticular arthritis, juvenile arthritis and juvenile dermatomyositis in relation to racial difference and sited references using dizygotic & monozygotic twins, concordance, penetrance and population studies. In depth knowledge about the significant association of RA and HLA DR4 halotypes, immune mediated blistering phemiphegus disease, multiple sclerosis and DRB1 & DQB was clearly acknowledged. The authors also revel into the aspect of transcomplementation of HLA dimers with additional reference to coeliac disease. The authors also thrive to explain the mechanism by which HLA may be attributed to autoimmunity and the concept of how disease associated alleles can give rise to unique peptide binding with reference to crystallography of binding pockets and how peptide binding motifs can be altered due to alleleic difference. Although there is prospect for new therapies, the authors also manage to mention some set backs such as the slow elucidation of the antigen processing mechanism and explained known factors that affect processing.

The texts also illustrate the molecular chaperone theory of HSP73 in connection to DR4 alteration in autoimmunity. Additionally the text dives into theories and hypothesis of MHC-TCR interaction with reference to crystal trimolecular complex. The concept of closely related alleles leads to protein that interact with similar TCR was well established with the importance of heterozygousity stressed using DRB/*0401/DRB/*0404 as example. The role of Molecular Mimicry was well explained with greater exploration into HLA B27 analogy to kleibsella, Pneumoniae, shigella sp. Emphasised. In-depth case studies of HLA B27 and spondyloarthropaties, Epstein Barr virus and Ecoli. Protein in Rheumatoid Arthritis and explains the prospective direction for precisely targeted Rheumatic therapy.

The prospects for new therapies were then deflected to (chapter 4) exploring the production of antibodies and the intracellular process that are involved in B-cell production. The role of auto antibodies (anti-DNA & anti-phospholipids) in rheumatic disease and the importance of expression systems in elucidating further mechanism and prospect for new therapies were well elaborated on. The author further explains the role of CD40 in B-cell proliferation (Chapter 5 &6), switching and tolerance. The role of CD28 CTLA-4 in T-cell activation, co-stimulation and inhibition in Murine and Man expression experimental systems was used to establish the present state of Rheumatology research.

The immunological mechanism was redirect to (chapter 7) Lymphocytes antigen receptor signal transduction systems with details on the tyrosine kinases involvement in TCR and BCR signalling and the aspect of calcium signalling with involvement of protein C, RAS/MAP pathway and the aspect of co-stimulation. The mechanism of action of adhesion molecules in inflammation and how they can be used as prospective therapeutic targets (Chapter 8) and the Regulation of apoptosis as a mechanism for the control of most rheumatic disease (Chapter 9) was also established. Further, the book also devoted a chapter (10) to one of the fastest growing aspect in Rheumatology; monokines in RA with detail on Interleukins 1, 6, 10, TNF and TGF_ with clinical trial data. In-vitro analysis and the proper explanation of markers such as proteoglycan and glycoasminoglycan were documented in the text. The authors also explore new horizon such as the role of the relatively less well documented IL-15 as an analogue of IL-2 in T-cell stimulation and concluded with a chapter (12) of Complements involvement in autoimmunity.

Although the book produces a sound immunological illustration that will enhance the understanding of rheumatic disease and the prospect for novel therapies, the effectiveness of this detail fine piece can be undermined by the monochrome nature of diagrams incorporated in the text. The text also lack flow of information between chapters (inter-chapter connection) as manifested as an inevitability of most multi-authored text. The flow of information in the text was affected by the extremely extensive in-chapter quotation of references. Even though the book is highlighted as the aspect for new therapies, the lack of homogeneity in explaining the role of present therapies in comparison to the prospects for new therapies in most chapters (e.g. 3,) has distorted the purpose of the books.

Although the molecular immunological basis of the most common Rheumatic diseases were well illustrated, the concept of future therapy was not well expanded and there was little or no explanation of the molecular basis of present drug interaction in rheumatic disease. Although this book provide a strong background in most aspect of autoimmunity, it does not implicate the modulation of diet status in autoimmunity as there is an increasing evidence of different dietary components modulating the effect of certain rheumatic diseases with reference to RA.

Although the scope of the book was limited to major rheumatic disease, there was little or no evidence of the molecular basis that implicate coagulation, fibrinolysis and or their pivotal regulatory substance in the text. This book provides a strong basis for any Rheumatic practitioner, Researchers interested in the molecular basis of Rheumatic disease. It is a very sound text that can enhance the understanding of the underlying cause of most rheumatic diseases.

By Sulaiman George Gegbe
Department of Clinical Haematology
West Suffolk Cambridge Postgraduate Teaching Hospital Trust
Hardwick Lane, West Suffolk, IP33 2QZ. &
Kingston University
Postgraduate Bio-Medical School
Kingston, U.K.
Sugees@angelfire.com

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