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The Immune Response
The innate and adaptive systems are two components of the immune system which act in concert to defend against foreign infections and promote healing following an injury. The innate response is the initial non-specific response to foreign antigen comprising cells of the macrophage monocyte lineage, dendritic cells, neutrophils, and complement. Macrophages and dendritic cells not only phagocytose / pinocytose foreign agents but also process the antigen for presentation and activation of the adaptive immune system. Macrophages demonstrate remarkable plasticity depending on the nature of the stimulus, resulting in anti- or pro-inflammatory responses. Dendritic cells share many characteristics of macrophages and are key antigen presenting cells, establishing an important link with the adaptive immune response.2 Surface and cytosolic toll like receptors (TLR), as well as cytosolic nucleotide-binding oligomerisation domain (NOD) like receptors (NLR) of dendritic and other antigen presenting cells, recognize and interact with numerous pathogen-associated molecular patterns (PAMPs) and damage-associated patterns (DAMPs). The adaptive response is a delayed, but specific response, comprising of T and B lymphocytes. The adaptive response is initiated by antigen presentation and activation of naive T cells. Depending on the stimulus and host environment, T cells differentiate into Th1 (cell-mediated response), Th2 (humoral /antibody-mediated response), Th17 (pro-inflammatory response) and regulatory T cells (Tregs) (inhibitory response). T cell activation results in a specific response and retention of memory to a particular antigen.
A crucial host factor is the major histocompatibility complex (MHC) or human leukocyte antigen (HLA) system which is encoded by the chromosomal area important for self-recognition, tolerance and displaying of antigens to T cells. The MHC is classified into 3 classes I, II and III. Class I comprises three groups A, B, C and class II is a single group, D, that is further subdivided into three, DP, DQ, and DR. Class I is found on all nucleated cells and plays a key role in self-tolerance and protection against viral infections. Class II is displayed on antigen presenting cells involved in regulating the immune response. Class III consists of genes encoding complement proteins and certain cytokines.
Functional changes to DNA without alterations in structure occur through biochemical processes resulting in epigenetic modulation of protein transcription. These biochemical changes include methylation and acetylation that can influence gene expression. Epigenetic changes may also occur following coupling and uncoupling of chromosomal nucleotides with certain polypeptides such as ubiquitin and ubiquitin-like peptide.
Cytokines are molecular messengers which play an integral role in the cross-talk between various components of the immune response and host, allowing for a co-ordinated and regulated response. Numerous intracellular signaling domains respond to these molecular signals and modulate the cellular response. Genetic factors including genotype and epigenetic changes often influence the ultimate cellular response.
CHAPTER 1 Introduction
1.1.1 The Immune Response
1.1.2 Cytokines and intracellular signalling domains
1.1.3 Cytokine receptors
1.1.4 Key cytokines and their signalling pathways
1.1.4.1 Pro-inflammatory
1.1.4.2 Anti-Inflammatory
1.2 Pathogenesis of rheumatoid arthritis Overview
1.2.1 Genetics of rheumatoid arthritis
1.2.2 Non-HLA genes
1.2.3 Epigenetic factors
1.2.4 Non genomic factors
1.2.5 Synovial Inflammation in RA
1.2.6 Immune Dysregulation
1.2.7 Cellular Proliferation
1.2.8 Disease perpetuation
1.2.9 Tissue damage
1.3 Biomarkers in RA
1.3.1 Clinical measures and acute phase response measures
1.3.2 Imaging markers
1.3.3 Genotyping
1.3.4 Autoantibodies
1.3.5 Novel laboratory markers
1.3.6 Comment
1.4 Rheumatoid arthritis in the developing world References
CHAPTER 2 Patients and Methods
2.1 Study design
2.2 Clinical and radiographic methods
2.2.1 Disease activity variables assessed
2.2 Functional assessment included
2.2.3 Radiology
2.3 Serum
2.3.1 Rheumatoid Factor (RF)
2.3.2 Anti-citrullinated peptide antibodies (ACPA)
2.3.3 Antibodies to modified citrullinated vimentin (anti-MCV)
2.3.4 Genotyping
2.3.5 Cytokines
2.3. Serum matrix metalloproteinase-3 (MMP-3) and cartilage oligomeric matrix protein (COMP)
2.4 Treatment
2.5 Statistical Analysis
2.6 Ethics
2.7 Funding obtained fro
References
CHAPTER 3 Serum matrix metalloproteinase-3 (MMP-3) in comparison with acute phase proteins as a marker of disease activity and radiographic damage in early rheumatoid arthritis
3.1 Introduction
3.2 Patients and Methods Patients
3.2.2 Laboratory Methods
3.3 Results
3.3.1 Demographic, clinical and laboratory data (autoantibodies, acute phase reactants, haemoglobin, ESR, MMP-3 and COMP)
3.3.2 Correlations of MMP-3 with clinical indices of disease activity and non-cytokine, inflammatory biomarkers
3.3.3 Correlations of MMP-3 with cytokines/chemokines/growth factors
3.3.4 Correlations of COMP with clinical indices of disease activity and non-cytokine inflammatory biomarkers
3.3.5 Association of MMP-3, SAA, CRP and COMP with SE
3.3.6 Correlations of CRP and SAA with clinical and laboratory indices of disease activity
3.4 Discussion
References
CHAPTER 4 Circulating anti-citrullinated peptide antibodies, cytokines, matrix metalloproteinase-3 (MMP3-) and cartilage metabolites as biomarkers of response to disease-modifying anti-rheumatic drug therapy in early rheumatoid arthritis
4.1 Introduction
4.2 Patients and methods
4.3 Statistical analysis
4.4 Results
4.5 Discussion
4.6 Conclusions
References
Conclusion
Appendix 1
Appendix 2
