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Unraveling the Immunologic Mechanisms of Relapsing Polychondritis

Jane Hoyt Buckner, M.D.

Virginia Mason Research Center

Benaroya Research Institute

Seattle WA 98101

Introduction

Relapsing Polychondritis (RP) is an uncommon disease with an

estimated incidence of 3.5 cases/million. The disease has been

described in individuals ranging from childhood to 90 years of age

but occurs most frequently between the ages of 40 - 60. The hallmark

of RP is chronditis (inflammation of cartilage) involving the ears,

nose and trachea. Inflammation at these sites can lead to cartilage

destruction and result in deformity of the ears and the nose and

obstruction of the trachea which leads to difficulty breathing. Other

inflammatory problems are seen in RP including: arthritis, eye

inflammation, hearing and balance disturbances, vasculitis, and

rarely kidney and brain involvement. In addition, up to 30% of

patients with the diagnosis of RP have another autoimmune disease.RP

is a disease that affects each individual differently, and may be

mild to severe. The diagnosis of the disease by a physician is based

on a set of clinical criteria, determined by the patients history,

physical exam and when possible a biopsy of the affected cartilage.

There is no specific blood test for this disease. Treatment is based

on our understanding of other autoimmune disease, and includes use of

NSAIDs, prednisone and immunosuppressive drugs. The cause of RP is

still unknown, but there are several lines of evidence that suggests

that an autoimmune response directed against cartilage may lead to

this disease. This evidence includes: the presence of both T cells

and antibodies at the site of inflamed cartilage, the presence of

antibodies directed against cartilage in the blood of patients with

RP, animal models of RP, and clinical observation that

immunosuppressive medications can successfully treat some patients

with RP.

RP is a disease for which there are many unanswered questions and

problems. The central question that we focus on in our research

is " What is the cause of RP? and How dose the immune system

contribute to this disease? " . To answer these questions we are

examining the immune system's response to cartilage in this disease.

But our work touches on more practical problems as well including:

1) How to diagnose and follow disease activity in patients with RP.

and 2) How to predict the disease course in each individual with RP.

We hope in the future to directly address the core question, how best

to treat patients with RP.

Research Program in RP

Understanding the cause of an autoimmune disease has many facets:

identifying the part of the immune system which is attacking the

bodies tissues, then identifying the target of abnormal immune

response, and identifying any gene which lead to disease. In RP there

is evidence that both the humoral (antibodies) and cellular (T cells)

arm of the immune system are involved in this disease. Blood samples

from individuals with RP allow us to test whether antibodies directed

against cartilage or T cells activated by cartilage are present in

RP. Our work to date has demonstrated that antibodies and T cells

directed against cartilage are present in some patients. We have

taken the next step, identification of the component of cartilage

causing the immune response. One such component is type II collagen,

the main protein in all cartilage. We have found that over 50% of

patients make antibodies, and 40-50% of patients have T cells

reactive to type II collagen. We have also identified a new cartilage

protein, matrilin-1, which causes an autoimmune response in some

patients. Intriguingly, this protein is only found in the cartilage

of the ear, nose and trachea, sites of the most inflammation in RP.

There are many component parts of cartilage, and we plan to continue

searching for other proteins that are targets for autoimmunity in RP.

Our ability to identify antibodies and T cell responses to type II

collagen, has further allowed us to study in fine detail the

character of the immune response to this protein in RP patients.

These details may allow us to understand the underlying problems with

the immune system in RP, and what drives it. Fortunately, we have

been able to follow the immune responses of these individuals over

that period. We hope that these changes may give us clues to what may

cause progression or remission of disease. The practical application

of these findings includes the development of new diagnostic tests,

the ability to follow disease activity and potentially predict

disease flares, and identify the best forms of immunotherapy.

Genes are known to play a role in many autoimmune diseases,

particularly in predisposing individuals to development of disease.

The HLA family of genes has shown to predispose to diseases such as

rheumatoid arthritis, systemic lupus, multiple sclerosis and juvenile

diabetes. We are examining the role these genes play in RP at this

time, and in the future we will be able to look at other genes that

play a role in autoimmunity.

In order to do this we must acquire blood samples from individuals

with RP. We have been very fortunate to have a large number of

individuals throughout the United States participating in this work.

We hope to expand the number of RP patients participating in the near

future. With a large group of participants we are able to make much

more headway into this disease. Since each patient can be affected in

different ways; severity of disease, the site of inflammation and

disease activity at the time we receive their sample, we also need to

have details information about each participant. To aid us in this

work we have now established a database with which to keep all of the

clinical and laboratory information on patients. This has been done

to improve our ability to examine and interpret dates, and also to

assure confidentiality for each participant.

Future Plans

We began our research in RP in 1997 with the goal of examining the

immune response to cartilage in individuals with RP> Due to the

larger group of RP patients in this work and the financial support

from individual donors and the Arthritis Foundation we plan to expand

our RP research program. We will continue to address the immunologic

mechanism and genetic contributions in RP, with hopes of

understanding the underlying disease process. Further, we also plan

to expand our clinical database in order to better predict what

patients with RP can expect in terms of their long term health and to

identify the role that factors such as previous illnesses, exposures,

or family history in disease development.

Support

This research is supported by a grant from the Arthritis Foundation

and by the Virginia Mason Relapsing Polychondritis Research Fund, and

The Constance Research Endowment Fund.

Recent publications related to Relapsing Polychondritis include:

Buckner, JH and Nepom, GT.: The role of MHC antigens in autoimmunity.

In Immunologic Aspects of Rheumatic Disease:

Cambridge Reviews in Clinical Immunology, J.S.H. Gaston, ed.

Cambridge University Press, 1998.

Buckner JH, Wu J-J, Riefe RA, Terato K and Eyre DR:

Autoreactivitiy against martilin-1 in a patient with relapsing

polychondritis. Arthritis Rheum Arthritis and Rheumatism, 43(4),

April 2000, 939-943.

Buckner JH, Kleeman-Fisher D, Wu J: Martilin-1 as an autoantigen in

relapsing polychondritis. Arhtritis and Rheum 1999 42:S 109#229

Buckner JH, Terato K, Reife RA, Wu J : The immune response to

cartilage patients with relapsing polychondritis. Arthritis and

Rheum 1999 42:S321#1500

Individuals who wish to participate in this research may contact:

Dr. Jane Hoyt Buckner, M.D.

1201 9th Ave.

Seattle, WA 98101-2795

phone

Email; jbuckner@v...

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