Immune System

Cellular Component	Normal Response
Genes	Cell markers located on the surface of all body cells, known as Major Histocompatibility Complex (MHC) proteins, help the body distinguish self from non-self. They are commonly known as Human Leukocytic Antigens (HLAs). The 6 specific HLAs within the MHC markers are: Class I Antigens: HLA-A, HLA-B, HLA-C - found on nucleated cells & platelets. Class II Antigens: HLA-DP, HLA-DQ, HLA-DR found on monocytes, macrophages, B cells, activated T-cells, vascular endothelial cells, skin cells and dendritic nerve cells. Class II HLA loci normally occur, however there are fewer positively charged amino acids at the DRB1 sites than in individuals with RA. Campbell 2003. Class III of Antigens: include complement proteins C2, C4 and factor B Goodman et al. HLA antigens are inherited and can predispose or increase an individual's susceptibility to autoimmune diseases. Not all people with the specific HLA pattern develop the disease, but those with the pattern have a greater probability of developing it than the general population. Goodman et al.
HPA axis	The HPA axis is stimulated when an antigen is recognized by the body. The axis limits the triggered immune response, hypothetically through a negative feedback loop. Morand 2001 It is considered the stress system of the body. Goodman et al If the HPA response is interrupted or damaged, individuals may be predisposed to the disease, or the severity of the disease may be increased. Morand 2001
Antigen	An antigen is any foreign substance in the body that is capable of triggering an immune response Goodman et al
Dendritic Cells	Dendritic cells are antigen presenting cells which present antigens on the surface of other immune cells. Dendritic cells also play an important role in the immune system by stimulating B and T lymphocytes and secreting cytokines to initiate the immune response. Banchereau 1998
C- reactive protein (CRP)	CRP is an acute phase reactant that is elevated when the body is fighting an antigen. It is responsible for clearing material released from killed microbes and cells. The concentration of CRP in the blood increases from 1 microgram/milliliter to as much as 1 milligram/milliliter during the disease process. Sharon
Cellular Component	Normal Response
Natural_Killer_Cells_(NK_cells)	Commonly called cytotoxic T cells or CD8, are large granular lymphocytes that recognize and destroy tumor cells. Their presence has also been shown to be a predictor of immune system functioning and longevity. (Goodman, Sansoni)
T-cells	Helper T-cells (CD4+) are the main component involved in the cell-mediated immune response. These T-cells are responsible for stimulating monocytes, macrophages and synovial fibroblasts to produce the cytokines IL1, IL6, and TNFalpha. They also secrete matrix metalloproteinases through cell-surface signaling (CD69 and CD11) and through release of INFgamma and IL17. Activated T-cells also stimulate B-cells to produce immunoglobulins (including rheumatoid factor) and stimulate osteoclastogenesis which causes joint damage. Choy, 2001
Th1/Th2	Th1 and Th2 secrete cytokines and inhibit each others effect. Th1 cells normally produce inflammatory cytokines (TNF alpha, IFN gamma, IL 2) which promote inflammation by activating MHC, which is found on the tissue macrophages. This activation of MHC in turn activates T or B lymphocytes. Th2 cells normally produce cytokines IL4, IL10 and IL13, which encourage B-cell production. Th1 and Th2 often cause excessive immune responses. Sharon
CD 3 & 4 & 8	Glycoprotein is expressed on the surface of helper T lymphocytes. On the T-cell, there is an antigen-specific T cell receptor (TCR) which is genetically programmed. Attached to the TCR are 5 polypeptide chains, three of which form the CD3 molecular complex. The CD3 acts to transmit signals into the T-cell after the TCR binds to the antigen (CD3 itself does not bind to the antigen). T-cells also express nonpolymorphic accessory molecules with a specific function, CD4 being one of these. CD4 molecules bind to the antigen (specifically, the nonpolymporhic parts of class II MHC molecules on the antigen). These helper T-cells with CD4 play an important role in recognizing/attacking class II MHC molecules. It is a "master regulator" in that it produces cytokines and interferons, increasing effects of macrophage function, and provoking proliferation of CD8 T cells. (Sharma, Awasthi, Collison, Haringer, Hawrylowicz, Liu) CD8 T cells provide defense against viruses and tumor cell growth by directly destroying infected cells. Kumar
B-Cells	A mature B-cell is known as a plasma cell. Plasma cells are part of the mature pannus and secrete rheumatoid factor and other auto-antibodies. Choy et al 2001
Plasma cell	Formed when the B-cell receptor recognizes a foreign substance or antigen. Plasma cells produce and secrete an antibody into the antigen. Capable of producing 5 types of antibodies: IgG, IgM, IgA, IgD, and IgE. Goodman et al
Cellular Component	Normal Response
Macrophage	When triggered by the immune cascade, they engulf pathogens and clean up debris produced by neutrophils. When further activated, they can stimulate angiogenesis along with lymphocytes and fibroblasts and act as antigen-presenting cells (APCs) to introduce the pathogen to lymphocytes. During the process of phagocytosis, the pathogen is marked with antigenic material to help cells recognize them as foreign invaders. The APC creates an epitope, a small portion of the processed pathogen, to present to a specific cell of the immune system known as helper lymphocyte (T4 lymphocyte). Macrophages are also involved in the defense against tumor cells by secreting molecules called monokines.Choy et al 2001, Goodman et al
Monocyte	Inflammatory molecules that become macrophages when they migrate to tissues. Goodman et al
Neutrophils	Part of the inflammatory cascade, neutrophils respond to infection and inflammation by releasing elastase and proteases which degrade proteoglycan in the superficial layers of cartilage Choy et al 2001. They also directly kill invading organisms via phagocytosis but can also damage host tissues. Neutrophils die after phagocytosis. Puss seen on wounds is an accumulation of dead neutrophils. White blood cells are the most numerous neutrophils and increase dramatically in the presence of an infection. Goodman et al
Prostaglandins	Monocytes and macrophages produce different types of prostoglandins. Prostoglandins increase vascular permeability, vascular dilation, and start neutrophil chemotaxis. Kuby Prostaglandins also increase the effects of agents such as histamine and bradykinin, and enhance pain perception Firestein^
Histamine	Histamine is released by chondrocytes, macrophages, T-cells, endothelial cells, and stromal cells. It has been shown to work with TNFalpha to promote proliferation and catabolic actions of synovial stromal cells and articular chondrocytes. Histamine also works with interleukins to stimulate T-cells & B-cells to promote the synthesis of immunoglobulins (some of which are auto-antibodies) ^^Choy 2001 Histamine binds with receptors on endothelial cells and stimulates vascular permeability. This allows other immune cells to enter the joint space. Sharon
Cellular Component	Normal Response
Cytokines	Mediate local intracellular communication for an integrated response to stimuli. It is part of the immune response allowing cytokines to bind to receptors on nearby target cells. TYPES: Pro-inflammatory: IL1, TNFalpha, IFNgamma, IL6, IL12, IL12, IL15, GM-CSF (granulocyte-macrophage colony stimulating factor), M-CSF (macrophage colony stimulating factor), MMP-1 and MMP-3 (matrix metalloproteinases), prostaglandins. Anti-inflammatory: IL10, TGFbeta, IL1ra, solTNF-R Choy et al 2001
TNF-alpha	Has 2 receptors: p75 and p55 and two main functions: 1. stimulate death domain proteins responsible for apoptosis and programmed cell death. 2. dominant activation of Nuclear Factor Kappa B (NF-kB), which is a key transcription factor for activating genes involved in inflammation. This includes: Cytokine production, collagenase and stromelysin stimulation, induced endothelial adhesion molecules, and osteoclast differentiation stimulated. Choy et al 2001
Interleukins	There are many types of interleukins (IL). Those important to the inflammatory process are listed below: IL1: a pro-inflammatory cytokine produced by monocytes and macrophages with actions similar to TNFalpha. IL-1 also regulates inflammation, controls body temperature and influences endothelial adhesion cells and macrophage activation. Playfair IL6: produced by T-cells, monocytes, macrophages and synovial fibroblasts; responsible for final maturation of B-cells to plasma cells, T-cell activation, proliferation of synovial fibroblasts, induction of acute-phase response, stimulation of growth and differentiation of hemopoetic precursor cells. IL11: production is induced by TNFalpha; stimulates development of osteoclasts which are responsible for bone degradation. IL10: produced by monocytes, macrophages, B-cells and T-cells; has been shown to inhibit the production of some cytokines (IL1 and TNFalpha) as well as the proliferation of T-cells in vitro. IL4: produced by CD4+ Th2 and helps with the differentiation of B-cells. In vitro studies show that IL4 inhibits activation of Th1 cells which in turn decreases production of IL1 and TNFalpha and decreases cartilage damage. IL7: produced by thymic stromal cells and functions to stimulate pre-B cell and T cell proliferation. (Chazen) Choy et al 2001
Cellular Component	Normal Response
Interferons	IFNgamma: cytokine made by T-cells that induces the expression of antigen-presenting molecules (Class II MHC) Choy 2001. INF gamma and TNF alpha: needed for an effective immune response against bacteria in the cell. IL-4 and IL-5 are responsible for the starting a humeral response Miossec
lymphocytes	Lymphocytes are leukocytes - white blood cells - with a nucleus. They are very important in adaptive immunity and circulate between blood and lymphoid organs. There are two types of lymphocytes, B and T. Both types of lymphocytes are produced from pluripotent stem cells in the bone marrow and mature in separate locations. (campbell) B cells mature in the bone marrow and T cells mature in the thymus. (Goodman) Karp
Serum Immunoglobin Concentration	Normalized levels
Mast cells	Contain TNFalpha which initiates the inflammatory cascade and promotes expression of IL1 and IL6. Tryptase and chymase are mast cell proteinases which activate the matrix metalloprotein precursors and degrading proteins. Choy et al 2001
Adhesion molecules	PROBABLY NEED TO EDIT SO MORE GENERAL; Expressed by endothelial cells and synovial fibroblasts ; increase recruitment of neutrophils and inflammatory cells into joints Choy 2001
Matrix Metalloproteinases	Mediate degradation of extracellular matrix. TYPES: A 26 member family of enzymes which degrade connective tissue matrix Choy 2001 MMPs are generally classified as collagenases, stromelysins, gelatinases, and membrane-type metalloproteinases. Produced by a variety of cells in response to inflammatory cytokines (IL-1, TNF). Initially when synthesized they are inactive; become active enzymes via a sequence of events perhaps starting with the activation of key proenzymes. Plasmin is hypothesized to play a major role in activating enzymes including Stromelysin-1. Stromelysin-1 then activates many of the collagenases. Together, MMPs degrade all components of the extracellular matrix. At physiological pHs the collagenases are the only enzymes known to be able to cleave collagen. Firestein