By Nabih I. Abdou, MD, PhD
Clinical Professor of Medicine
Vasculitis Foundation Medical Consultant
Presented at the All Star Vasculitis Symposium
Why do we need to know about mechanisms of vasculitis?
To identify and target our treatment towards the main mechanism(s) that lead to vasculitis and be able to have a marker for vasculitis that could be of value in the diagnosis and follow up of progression or improvement of vasculitis patients.
Several mechanisms could play a role by themselves or in combination in the induction and progression of vasculitis including genes that are inherited. For example, antineutrophil cytoplasmic antibody and cells that make up the immune system, including T cells, B cells, dendritic cells, and vascular endothelial cells. Immune complexes made up of antigen-antibody complexes could also play a role. Moreover, infections such as viruses, bacteria, fungi, parasites, could participate in the induction and/or progression of certain types of vasculitis. Environmental factors such as pollutants, occupational hazards, have been reported to contribute to the initiation or aggravating vasculitis. Race and geographic location could also play a role in certain types of vasculitis such as Behcet’s which is prevalent in the Mediterranean countries and theFar East.
Genes in Vasculitis: Why do we need to know about the genes in vasculitis patients?
We could possibly predict in the future susceptibility to vasculitis, help in understanding how the genes influence susceptibility to vasculitis, and improve the efforts in designing treatment. The field of pharmacogenetics will soon be important in understanding why some vasculitis patients respond differently to medications. Moreover, recent reports have indicated that certain genes such as PR3 gene expression increases in active Wegener granulomatosis (WG). That may lead—in the future—to look in ANCA-associated vasculitis for PR3 gene expression and not only to test for serum ANCA level.
Recent discoveries have shown the predominance of certain HLA (human lymphocyte antigens) in certain types of vasculitis, for example, HLA‑DRB4 in Churg Strauss syndrome (CSS); HLA-B8, HLA-DR2, and HLA-DQ7 in WG; and in microscopic polyangiitis (MPA), and HLA-B51 in Behcet’s.
There is no evidence that vasculitis is inherited, e.g., there is no familial aggregation in WG. You should not worry about catching vasculitis if you are married, or planning to get married, to a vasculitis patient. We need to conduct population studies on a large number of patients, particularly twins, to get meaningful data about genes and inheritance. We should not look at all types of vasculitis and assume that they all have one mechanism to cause the disease. Mechanisms that play a role depend on the type of vasculitis, e.g., autoantibodies are markers and could play a role in disease damage, e.g. proteinase 3 (PR3) antibody in WG and myeloperoxidase (MPO) antibody in MPA.T cells have been shown to play a role in Giant cell arteritis (GCA) and immune complexes are present in the circulation and at the sites of vasculitis damage in cryoglobulinemic vasculitis.
Autoantibodies in Vasculitis:
Testing for autoantibodies has been helpful in the diagnosis of certain types of vasculitis, e.g., positive ANCA will assist and confirm the diagnosis in WG, MPA, and CSS. We should combine both immunofluorescence of blood neutrophils and serum immunoassay to be sure about the diagnosis in ANCA-associated vasculitis. A negative ANCA test does NOT exclude ANCA-associated vasculitis. ANCA positive patients, however, who become ANCA-negative is a good prognostic feature and ANCA-negative patients who become positive are at increased risk of disease flares. Therapy of ANCA-associated vasculitis should not be dependent on ANCA blood serology and titer alone.
Vasculitis mechanisms could be one or more of the following:
Antibody mediated in ANCA-associated vasculitis (WG, MPA and CSS).
T cells and their various types such as T4, T8, T regulator cells and TH17 in GCA, Takayasu’s arteritis, and WG.
Antigen-antibody ± complement and their role in hepatitis C induced cryoglobulinemic vasculitis and in hepatitis B in Polyarteritis nodosa (PAN); the latter has not been validated yet.
Antineutrophil cytoplasmic antibodies (ANCA) could be in two forms:
PR3 antibody is present in Azurophil granules of neutrophils and peroxidase positive lysosomes of monocytes. Myeloperoxidase (MPO) is present in neutrophils and monocytes. Both PR3 and MPO antibodies are directed against multiple sites (epitopes) of the target antigen. Understanding the role of various epitopes on the antigen molecule might lead us to understand the various clinical manifestations of a disease, e.g., in WG, why some patients have predominant kidney disease whereas others have predominant sinus or lung disease. Do these manifestations correlate with different forms or sites on the ANCA antibody?
Immune cells in vasculitis:
Our current information on immune cells in vasculitis is incomplete. We need to perform more studies to understand if the cells at the site of vasculitis are the cause of or secondary to vasculitis. We need information on the specificity of the cells to vessels. That will require investigators to perform experiments to transfer to certain animal models, vessels or cells involved in vasculitis and check if we can reproduce the disease in the animal model and to understand the sequential events in the induction and progression of vasculitis.
Preliminary recent data on T cells in GCA showed that T cells are present in the adventitia (perivascular) of vessel wall. Transfer of T cells in proper animal models could reproduce the disease under the proper conditions. More work needs to be done to characterize those cells and understand the natural immunity (toll-like receptors) in the vessel wall. These investigations will lead to progress in understanding the selective distribution of vasculitis in certain vessels, e.g., aorta in Takayasu’s, coronary arteries inKawasakiarteritis, and temporal artery in GCA.
New discoveries indicate the role of a new type of T cell called T regulator cells in controlling hepatitis C induced mixed cryoglobulinemic vasculitis. A positive correlation was found between improved disease and levels of hepatitis C specific T regulatory cells. The latter cells were found to play a role in disease remission of ANCA-associated vasculitis by producing interferon-γ.
T cell immunology is contributing to our understanding of the mechanisms in vasculitis by discovering a new type of T cell called TH17 lymphocytes. At the present time, T cell biology has shown that there are three types of T cells:
- TH1 cells produce interleukin (IL) 2, gamma (γ) interferon (INF) and play a role in cellular immunity.
- TH2 cells produce IL-4, IL-5 and play a role in allergic response.
- TH17 cells produce IL-17 and play a role in autoimmune inflammation and in vasculitis disease pathogenesis. Therefore, investigators in vasculitis are looking for new therapeutic targets to block IL‑17.
Immune complex mediated vasculitis is shown to play a role in certain types of vasculitis as in drug-induced hypersensitivity vasculitis; cryoglobulinemic vasculitis with hepatitis C infection; Henoch-Schönlein purpura (HSP) (with IgA deposits in vessels, and hypocomplementemic urticarial vasculitis.
Understanding the role of immune complexes in cryoglobulinemic vasculitis is important and helpful in designing treatment to remove the immune complexes, e.g., by filtering out immune complexes or by plasmapheresis.
Understanding the mechanism(s) in mixed cryoglobulinemic vasculitis associated with hepatitis C opens the doors for possible successful therapy with rituximab to remove B cells or by pegylated interferon alfa or by the use of Ribavirin to remove the viruses. This approach is usually done following plasmapheresis or immunoadsorption and resulted in encouraging results in very serious debilitating aggressive forms of vasculitis.
Infectious causes of vasculitis:
Certain types of vasculitis are caused or are associated with infectious agents, e.g., hepatitis C virus in cryoglobulinemic vasculitis; hepatitis B in some PAN patients. Kawasaki disease has several features of infection including fever and lymphadenopathy. These observations would indicate that an exogenous agent could have activated one clone of immune T cells. So far, an infectious agent has not as yet been detected inKawasakidisease.
Is vasculitis an autoimmune disease?
Classical immunology teaches us that the strict definition of a disease to be labeled as an autoimmune disease should fulfill the Witebsky criteria. These criteria include the detection of an antigen; detection of autoantibody; the autoantibody can transfer the disease to experimental animals or humans and then to demonstrate the presence of the transferred autoantibody in the recipient animal at the site of vasculitis.
Therefore, at the present time, human vasculitis does not fulfill the classical strict criteria for an autoimmune disease. THIS comment is going to raise aLOT of questions/concerns with patients. They have been told that vasculitis is an autoimmune disease and all of the VF’s literature calls it an autoimmune disease. This would be a loose definition of the term autoimmunity.
Why do we need to know if vasculitis is an autoimmune disease?
This will help in understanding the mechanism of vasculitis; how the vessel damage occurs, evaluate the severity of the disease, help in selecting the type of treatment; whether we need to target B cells, or target T cells, or by targeting immune complexes by plasmapheresis or by immunoadsorbent columns.
Why do we need to know about autoantibodies in vasculitis?
Detecting specific autoantibodies in vasculitis will help in diagnosis and in monitoring disease progress and understanding how autoantibodies damage tissues or organs in vasculitis, and hopefully in the future to understand the specificity of the autoantibody that could explain the various manifestations of the disease.
In certain types of vasculitis, great advances have been made once an autoantibody was detected, e.g., the role of ANCA in ANCA-associated vasculitis helped in understanding the mechanism of vasculitis, and how an autoantibody induces vasculitis. We still need long-term studies to clarify the autoimmune mechanisms in the various forms of vasculitis.
Summary of mechanisms that could play a role in vasculitis and future goals and hopes:
Genes: inheritance, family studies, particularly twins, need to be done at the present. This would be the first step before the gene(s) for vasculitis are discovered.
Antibodies, e.g., ANCA (antineutrophil cytoplasmic antibody). We hope in the future more antibodies will be detected as markers for other forms of vasculitis.
Cells: T cells, B cells, dendritic cells, vascular endothelial cells. This area could be expanded, particularly that specific immune markers are now available for cells using monoclonal antibodies.
Immune complexes: antigen-antibody-complement complexes. Will justify certain types of therapy.
Infections: viruses, bacteria, etc. This area is still in its infancy, but could be very promising in certain types of vasculitis, particularly by using the new technology using polymerase chain reaction (PCR) and microarray.
Environment: pollutants, occupational hazards, air, water, foods. We hope geographical prevalence of certain types of vasculitis and the vasculitis survey will give us some clues in that area.
Final remarks and request to all vasculitis patients:
Please participate in vasculitis research, if asked, in order to make progress in understanding the mechanisms that could play a role in inducing activity or causing tissue or organ damage in vasculitis. This research will result in progress in understanding why people get vasculitis, how we achieve early diagnosis, what are the best tests for diagnosis and the best therapy of vasculitis. We have made progress in the last few years, but our goals have not been met. The expected progress will lead to early diagnosis of vasculitis, better quality of life for vasculitis patients, and, hopefully, better and safer treatment to achieve remission of vasculitis.