How does HLA-B27 lead to ankylosing spondylitis?

April 18, 2011

HLA-B27 gene is closely related to Ankylosing spondylitis. It is found in almost 70-90% of patients with Ankylosing spondylitis.

HLA B27 stands for Human Leukocyte Antigen 27. The HLAB 27 gene produces the HLA B27 molecule, which belongs to the family of MHC class I molecules. The function of this family of molecules is to present antigenic peptides to the T cells.

Let us understand this process of antigen presentation further. Whenever a pathogen (bacterium/ virus) enters the body, body’s immunity recognizes these as foreign. The next step is to inform the other immune cells about these pathogens & provide them with sufficient information about the pathogens. With this information, immune cells then launch an attack against these pathogens. This information about the pathogens consists of parts of the pathogen (called antigens) & is presented by the antigen presenting cells to the T cells. These parts are the signatures of these particular virus/ bacteria. The T cells can trace the location of these pathogens based on the signature antigens they have & launch an attack on them.

Now, let us focus on what happens inside these antigen presenting cells. The signature antigens are given final touches in a structure called proteosomes. The final antigens are carried to another structure called the Endoplasmic reticulum where they are mounted onto the MHC class I molecule. The MHC molecule folds & is then taken to the surface of the cell. This complex is presented to the T cells, which then recognize it & mount an attack on the pathogen. The T cells do not recognize the antigens in absence of the HLA molecule.

A few pathogens have antigens that are similar to proteins in our joints. When such pathogens (eg. Yersinia, Chlamydia) enter the body (generally the gut & cause loose motions), their antigens are picked up by the antigen presenting cells. It is hypothesized that HLA-B27 tends to pick up the particular antigens in the pathogen that are similar to the joint proteins & present them to the T cells. T cells recognize these as foreign & attack any structure with these proteins. The pathogen is definitely taken care of; but as I said, T cells also start considering our joints as foreign & attack them as well. This is precisely what happens in reactive arthritis (ankylosing spondylitis & reactive arthritis belong to the same group of arthritis). In reactive arthritis, one has loose motions followed by joint inflammation. This is called the ‘Arthritogenic peptide hypothesis’

There is an alternative hypothesis to explain the cause of joint inflammation. This is called the HLA-B27 folding hypothesis. The difference between HLA-B27 & the other HLA molecules is that B27 has a slower rate of folding & is prone to misfolding. When this happens on a large scale, the endoplasmic reticulum malfunctions & triggers generation of cytokines (TNF-α, IL-1, IL-6). These cytokines attack the joint & cause inflammation. This sequence of events has been shown in cells of the synovial fluid in patients.

This is how the HLA-B27 positivity; in the presence of infections/ environmental factors translates into inflammation of the joints (spine & other joints) & ultimately manifests as ankylosing spondilytis/ reactive arthritis.

References:
Mear JP, Schreiber KL, Munz C, Zhu X, Stevanovic S, Rammensee HG, et al: Misfolding of HLA-B27 as a result of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies. J Immunol 163:6665–6670, 1999

Smith JA, Märker-Hermann E, Colbert RA: Pathogenesis of Ankylosing spondylitis: current concepts. Best Pract Res Clin Rheumatol 20:571–591, 2006

Turner MJ, Sowders DP, DeLay ML, Mohapatra R, Bai S, Smith JA, et al: HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response. J Immunol 175: 2438–2448, 2005

Robert A., Monica L., Erin I.: From HLA-B27 to spondyloarthritis: a journey through the ER Immunol Rev. 2010 January ; 233(1): 181–202

Benjamin R, Parham P. Guilt by association: HLA-B27 and ankylosing spondylitis. Immunol Today 1990: 11: 137–42.

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Do we really need a separate blog corner for Ankylosing spondylitis?

April 11, 2011

Ankylosing spondylitis (AS) belongs to the spondyloarthropathy group of arthritis that also includes reactive arthritis & psoriatic arthritis. As a group it is as common as Rheumatoid arthritis.

However; Ankylosing spondylitis, somehow, has always been a bit ignored as compared to Rheumatoid Arthritis (RA). It is has been that ‘poor cousin’ of RA. If you look at the number of research papers in a year, one would realize that AS attracts much less research than RA (about 2500 research papers on RA as compared to about 500 on AS in the year 2010- source pubmed). The number of DMARDs available for AS is much lesser than RA. We have clear-cut treatment strategies (for eg. Early DMARDs, tight inflammation control) in RA; however, due to relative lack of studies, such strategies are missing in AS.

Even on the patient/ health care social media (hcsm) front, there are very few AS blogs as compared to RA blogs.

This is a humble effort from my side to bridge this gap & empower the Ankies (Those with Ankylosing spondylitis; just like RAers!) to take care of themselves.


Stem cell therapy for Rheumatoid Arthritis

April 3, 2011

Rheumatoid arthritis (RA) is an autoimmune disease. For unknown reasons, one’s own immune system starts thinking that his/ her joints are foreign & attacks them. This results in inflammation of the joints. The routine treatment includes medications that modulate the immune system (DMARDs) or medications that block the cytokines (biologics).

We are in the age of organ transplant. Kidney transplant has become an established therapy for those with kidney failure. How about immunity transplant since RA is an immune dysfunction. This is precisely what led the scientists to try out stem cell therapy for RA.

Unlike kidney, the immune system is not a solid organ that can be removed; hence chemotherapy is used to ablate the marrow (organ where the immune cells are generated). This is followed by infusion of stem cells. The stem cells give rise to a whole new immune system that does not attack the joints.

Geoff McColl first reported a successful stem cell therapy in a man with resistant RA in the October 1999 issue of Annals of Internal Medicine. A 39-year-old man with RA who had failed standard RA therapy was treated with stem cells from his identical twin brother. The results were dramatic & the patient could swim, ride a bicycle & was free of RA symptoms even after 2 years of the therapy.

Richard K. Burt also reported about a successful stem cell therapy in a lady with resistant RA in the August 2004 issue of Arthritis & Rheumatism. A 52-year-old lady with treatment resistant RA was treated with stem cells from her sister. She remained in remission even after 1 year of stem cell therapy. Her rheumatoid factor disappeared & so did the rheumatoid nodules. The joint inflammation & the morning stiffness settled & the ESR normalized.

However, this is easier said than done. These stories sound fabulous. Studies were taken up to study this therapy further. A study from Netherlands included 14 RA patients. Of the 12 who completed the study, 8 patients improved significantly within one year of therapy. 4 patients failed to respond & those who had responded relapsed & required reinstitution of DMARDs within 2 years of therapy. Snowden J & colleagues analysed the registry data of 76 patients who received the therapy in different studies. In most patients, disease-modifying anti-rheumatic drugs had to be reinstituted within 6 months for persistent or recurrent disease activity.

Zhang-Huo li and a team of researchers from Peking university People’s Hospital have come with a new approach recently. They studied the umbilical cord mesenchymal stem cells. They found that these cells can suppress the inflammatory effects of RA related fibroblast-like synoviocytes and T cells in cultures. They also showed promising results in animal models of inflammatory arthritis.

All in all, stem cell therapy for RA is in a developing phase. We will have to wait for further studies with different medications/ designs for a definitive take on this approach.

References:
High-Dose Chemotherapy and Syngeneic Hemopoietic Stem-Cell Transplantation for Severe, Seronegative Rheumatoid Arthritis Geoff McColl et al October 5, 1999 131(7) 507-509

Verburg RJ, Kruize AA, van den Hoogen FH, et al. High-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with rheumatoid arthritis: results of an open study to assess feasibility, safety, and efficacy. Arthritis Rheum. 2001;44:754-760.

Snowden J, Moore J, Passweg JR, et al. Autologous stem cell transplantation in rheumatoid arthritis. Blood. 2001;98:860a.

Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis. Liu Y et al Arthritis Res Ther. 2010;12(6):R210


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