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Rheumatoid Arthritis—A Molecular Understanding

J. Bruce Smith, MD; and Mark K. Haynes, PhD
[+] Article and Author Information

From Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.


Acknowledgments: The authors thank Drs. John Abruzzo, Pam Norton, Andrew Koenig, and Stacy Fitch for their careful review and helpful suggestions in the preparation of this manuscript.

Grant Support: By the Mona Schneidman Foundation.

Requests for Single Reprints: J. Bruce Smith, MD, Jefferson Medical College, 613 Curtis Building, Philadelphia, PA 19107.

Current Author Addresses: Dr. Smith: Jefferson Medical College, 1015 Walnut Street, Suite 613–Curtis Building, Philadelphia, PA 19107.

Dr. Haynes: Jefferson Medical College, 1015 Walnut Street, Philadelphia, PA 19107.


Ann Intern Med. 2002;136(12):908-922. doi:10.7326/0003-4819-136-12-200206180-00012
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The application of molecular immunology techniques in the study of rheumatoid arthritis has resulted in an explosion of knowledge on the risk factors for the disease, predictors of disease severity, the molecular mechanisms of inflammatory responses, and mechanisms of tissue destruction. We know, for example, that inheriting certain genes in the major histocompatibility complex partly dictates susceptibility and severity of rheumatoid arthritis. These genes and others in the major histocompatibility complex are critical for the occurrence of immune responses both constructive (prevention of infection, surveillance for malignant cells) and destructive (development of autoimmune diseases). We also now understand mechanisms of cell communication, regulation of immune responses, how the cells that mediate immune responses and tissue injury accumulate in tissues, and how the injury occurs. The knowledge itself is satisfying, but more important, based on this knowledge, effective and reasonably safe treatments that address basic mechanisms of the disease process have been developed and are now widely used. In fact, the newer treatments represent the “tip of the iceberg,” and as our basic knowledge increases, so too will the armamentarium with which we can fight rheumatoid arthritis and other similar autoimmune diseases.

For definitions of terms, see Glossary at end of text.

Figures

Grahic Jump Location
Figure 1.
Interactions between T cells and antigen-presenting cells. A.B.C.

Polypeptide antigen undergoes pinocytosis by an antigen-presenting cell and is enzymatically digested; small peptides are then associated with a class II–related molecule in the cell and subsequently inserted with human leukocyte antigen class II α and β chains on the cell surface. Small peptide antigens may bind directly to surface class II molecules. The antigen-presenting cells interact with a passing T cell that bears the appropriate T-cell–antigen receptor—that is, one that “fits” the T-cell receptor. Antigen-presenting cells and T cells are held together by cell interaction molecules LFA-1/ICAM-1 and costimulatory molecules B7/CD28. T cells and antigen-presenting cells become activated to produce cytokines. Activated T cells and antigen-presenting cells continue to produce cytokines and other mediators of inflammation. CD = cluster of differentiation; FAS = fatty-acid synthesis; LFA = lymphocyte function antigen; ICAM = intercellular adhesion molecule; IFN = interferon; IL = interleukin; MHC = major histocompatibility complex; NO = nitric oxide; TNF = tumor necrosis factor.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Class II molecules of the major histocompatibility complex (top and side views).

The antigen-binding cleft formed by the intertwining of the α and β chains of the molecule shows the peptide sequence known as the “shared epitope” in the β chain (shown as the cross-hatched area). The shared epitope is specified by the disease-associated allele in genes associated with rheumatoid arthritis (for example, human leukocyte antigen DR4). The shared epitope may serve as the binding site for an arthritogenic peptide or may itself be the autoantigen that activates T cells. ICAM = intercellular adhesion molecule.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Lymphocyte adhesion and migration into tissues. A.B.C.LFA-1ICAM-1D.Bottom.22

and At or near sites of inflammation or tissue injury, L-selectin–positive lymphocytes interact with glyCAM-1 on vascular endothelial cells. This interaction causes lymphocytes to adhere loosely to the endothelium, roll along, and slow down. As the lymphocytes progress along the endothelium, they become attached in a more shear-resistant fashion through interaction between lymphocyte function antigen-1 ( ) on lymphocytes and intercellular adhesion molecule-1 ( ) on endothelial cells. Lymphocytes leave the vessel and enter tissues through gap junctions between endothelial cells. As shown in Figure 1, T cells are activated at sites of tissue inflammation through interaction with resident antigen-presenting cells. The resultant cytokine secretion attracts other cell types to the area and mediates tissue damage (in the case of rheumatoid arthritis and in other similar autoimmune diseases), clean-up functions (in the case of infections), or tissue repair (after injury). GlyCAM = glycosylation-dependent cell adhesion molecule; H O = hydrogen peroxide; IL = interleukin; NO = nitric oxide; TNF = tumor necrosis factor.

Grahic Jump Location
Grahic Jump Location
Figure 4.
Synovial cell proliferation, damage of cartilage, subchondral bone, and periarticular tissues in rheumatoid arthritis. A.B.12322

Normal joint. Joint affected by rheumatoid arthritis. The various aspects of immune activation and lymphocyte and neutrophil attraction to sites of inflammation (as discussed in the text and in Figures , , and ) act in concert to produce the clinical signs of joint inflammation and damage. H O = hydrogen peroxide; IFN = interferon; IL = interleukin; NO = nitric oxide; TNF = tumor necrosis factor.

Grahic Jump Location

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