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リウマチ Vol.41 No.2 indexに戻る
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リウマチ Vol.41 No.2 |
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「Systemic Vasculitis：Changing Concepts
in Pathogenesis and Treatment」 |
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| Gary S. Hoffman, M. D |
| Director, Center for Vasculitis Care and Research,
Harold C. Schott Chair
for Rheumatic and Immunologic Diseases, Cleveland Clinic Foundation |
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| 招請講演 |
Progress in systemic vasculitis
has suffered from the cause of illness usually being unknown and
treatment being only palliative. Recent
progress has occurred in understanding aspects of immune susceptibility
and how environmental factors, such as infectious agents may be involved
in expression of vascular inflammatory abnormalities. This presentation
will review changing concepts from the point of antigen presentation
to variations in immunoregulation that may improve our understanding
of “autoimmunity" in general, and vasculitis, in particular.
Persistent inflammatory/immunologically-mediated responses are well
understood in the setting of inadequate or “frustrated" phagocytosis.
Molecular approaches to the study of phagocytosis have helped elucidate
the role of receptors called “pathogen-associated molecular patterns（PAMPs)",
in facilitating antigen or particle engulfment, internalization and
degradation. Studies to determine whether these mechanisms are aberrant
in systemic vasculitides have not been undertaken. The cellular components
of innate immunity（macrophages, dendritic cells）may also function
beyond phagocytosis, through antigen presentation via MHC, to initiate
immunologic memory and produce an enhanced immune response. In individuals
who are normal, the learned immune response is specific for foreign
antigens and excludes “self" determinants. This phenomenon,
recognized as tolerance, is in part related to clonal deletion during
embryogenesis. Although it has been speculated that autoimmune diseases
may be related to selective loss of self-tolerance, definitive proof
of this concept in vasculitis does not exist. It has been suggested
that tolerance may be “broken" by infectious agents that mimic
host antigens. This may result in antibody production, with specificity
for foreign antigen homologous to self-Ag, which leads to cross reactivity（Albert
LJ, Inman RD：N Engl J Med 1999；341：2068).
Immunologic health is recognized by the presence of an intricate
balance between agonists and antagonists. For example, the macrophage
products IFNγ and TNF usually lead to enhanced lymphocyte, neutrophil
and endothelial cell activation, while IL4, IL10 and TGFβ generally
inhibit these events. Among lymphocytes Th1-type cytokines are antagonistic
to Th2-type cytokines. These interactions are critical in providing
for an orderly response to foreign antigens, as well as limiting
that response in time and place, so that innocent-bystander injury
does not occur in surrounding tissues. Macrophages present antigens
to CD4＋pre-T cells（through MHCII), which upon receiving a second
signal（macrophage B7 ligation to lymphocyte CD28）will differentiate
into Th1 or Th2 lymphocytes. In general, the role of Th1-type lymphocytes
is to mediate delayed hypersensitivity, while that of Th2 lymphocytes
is to provide “help" for B cells and inhibit delayed hypersensitivity.
In contrast, CD8 T cells when activated（with presentation of Ag through
MHCI）are directly cytotoxic, especially for virally infected cells.
Once the mediators of cell activation have been released, a reverberating
circuit of enhanced immunologic reactivity continues, until either
the antigen is cleared, leading to apoptosis of immune activated
cells that no longer bind antigen, or until counter-regulatory cytokines
come into play.
Evidence has emerged to indicate that imbalance in these mechanisms
plays a role in persistence of an abnormal immunologic response.
For example, in a subset of patients with Wegener's granulomatosis,
it has been demonstrated that down-regulating cell surface ligand
on T cells（CTLA4）may not be produced in adequate quantities to effectively
counteract the enhancing effects of B7→CD28 ligation（Huang D, et
al：J Rheumatol 2000；27：397). It is particularly intriguing to note
that “knock-out" mice for the CTLA4 gene develop lymphoproliferative
disease and vasculitis. Recognition of this defect in at least some
patients with Wegener's granulomatosis has raised questions about
the potential utility of CTLA4-Ig（fusion protein of CTLA4 and IgG1）as
a therapeutic agent. The efficacy of CTLA4-Ig has already been demonstrated
in prolongation of graft survival in animal models of transplantation,
murine lupus, diabetes in NOD mice, experimental allergic encephalomyelitis
and autoimmune myasthenia gravis. CTLA4-Ig is now in clinical trials
in psoriasis and rheumatoid arthritis.
IL1 is principally produced by macrophages and epithelial cells.
It is known to enhance activation of numerous cells including endothelial
cells and lymphocytes. Endothelial cell activation results in increased
release of adhesion molecules for leukocytes. Activation is mediated
by IL1 binding to the IL1 receptor on target cells. IL1 binding to
T cells and macrophages leads to cell activation. The activation
process on endothelial cells and lymphocytes is in part limited by
the IL1 reception antagonist（IL1ra), a product of monocytes, macrophages,
neutrophils and hepatocytes. IL1ra does not generate an intracellular
signal and is thus antagonistic to IL1（Nicklin JH, et al：J Exp Med
2000；191：303). Knock-out mice for IL1ra, as expected, clear antigens（e.
g. Lysteria monocytogenes）more rapidly than mice with intact IL1ra.
Certain strains of mice（C57 Bl/6×MF1）that are IL1ra knock-outs experience
premature death due to large vessel vasculitis. It is noteworthy
that vasculitis occurs in areas of greatest turbulence of blood,
at vessel flexures and branch points. It appears that this form of
large vessel vasculitis is at least in part due to inadequate counter-regulation
of IL1 activity. It would be important to determine whether a correlate
of this abnormality exists in man. It is of interest to note that
IL1ra knock-outs in different strains of mice, such as BALB/C or
DBA/1, results in severe chronic inflammatory polyarthritis（RA-like),
whereas the same knock-out state in C57 BL/6J appears to be inconsequential.
These observations emphasize the profound importance of variations
in “immunologic soil"（Horai et al：J Exp Med 2000；191：313).
Enhanced TNF production has been recognized in a variety of vasculitides,
particularly Wegener's granulomatosis. TNF is one of the pro-inflammatory
cytokines produced by monocytes, macrophages, Th1-type lymphocytes
and even remodeling injured myocardium. Although the exact reasons
that increased production of TNF occurs in certain diseases has not
been elucidated, it has been assumed that TNF expression is pathological
and not a compensatory healthy response to injury. This has led to
use of anti-TNF therapies in diseases such as rheumatoid arthritis,
Crohn's disease, spondyloarthropathies, congestive heart failure,
and most recently, Wegener's granulomatosis（WG). Thus far, in WG
only phase I studies have been performed. Early results suggest that
therapy is relatively safe possibly efficacious. Randomized double-blind
controlled studies are currently underway.
Increasing numbers of investigations are in progress to explore
the role of infection in either triggering or perpetuating autoimmune
diseases, including systemic vasculitis. Because many pathogens that
have been associated with vasculitis usually produce other disease
phenotypes（not vasculitis), it has been assumed that vasculitis in
conjunction with hepatitis viruses, parvo B19, HIV, CMV or Epstein
Barr virus is probably more a function of the host response, than
the pathogen itself. Support for this concept also comes from observations
of vasculitis in immunocompromised patients, including individuals
with X-linked lymphoproliferative syndrome and Epstein Barr virus
infections. It would appear that the presumed “permissive" immunologic
lesion for vasculitis would be more unique than the mere presence
of profound immunosuppression, as occurs in HIV infection, in which
most patients do not develop vasculitis.
Further support for these concepts of “seed and immunologically
appropriate soil" comes from the work of Dr. Herbert Virgin's
laboratory（Weck et al：Nature Med 1997；3：1346). This group has had
a long-standing interest in the role of g herpes viruses（gHV）（including
EBV and Kaposi's sarcoma herpes virus). A murine gHV（HV68）that shares
significant homology to human gHVS, is naturally occurring in wild-type
mice. HV68 is generally not a significant pathogen and upon infection
is readily cleared or maintained in a latent state. However, in studies
of similar mice in which the gene for IFNg or IFNgR is knocked out,
persistent viral replication leads to a fatal form of vasculitis.
If, instead, the perforin gene is knocked out, the same virus will
not produce vasculitis, but will cause lymphoproliferative disease.
It is observations such as these that have led to studies of immune
profiling of patients who develop systemic vasculitides and other
“autoimmune disorders".
One might argue that because immunosuppressive therapy（ISRx）is palliative
in the systemic vasculitides, infection would be unlikely because
ISRx would lead to death from infection. The example of parvo virus
infections in Aleutian mink urges caution in this perhaps over-simplistic
view of vasculitis. Twenty-five percent of wild-type Aleutian mink
will develop a chronic viral illness that includes proliferative
glomerulonephritis and necrotizing vasculitis. Treatment with cyclophosphamide
prevents vasculitis in these animals and prolongs survival, without
eliminating viremia.
Others have argued that rigorous attempts to identify pathogens
in autoimmune diseases have almost always failed and therefore the
likelihood of an infectious etiology for vasculitis is low. New developments
in molecular techniques, utilizing broad-range PCR in search of conserved
genes that identify broad groups of bacteria, viruses or fungi has
shed additional light on this issue. Surveys of terrestrial and aquatic
ecosystems have demonstrated that over 99％ of micro-organisms that
can be identified by these techniques resist cultivation in the laboratory（Relman
D：Science 1999；284). Consequently, molecular approaches of this type
are being increasingly applied to better understand the pathogenesis
of a variety of idiopathic diseases. There are limitations in this
approach. Tissue injury from infection could be related to toxins
and not the pathogen itself. The agent that initiated the pathologic
response may have been cleared at the time that the patient presents
with illness. In this setting, one may only be able to identify the
results of injury and still not find the cause, even by using these
exquisitely sophisticated molecular techniques. Under these circumstances,
it is hopeful that analysis of patterns of injury in affected tissue
may enable identification of specific causes of illness.
These approaches to better understand immune predisposition and
pathogen discovery are currently being employed in several laboratories.
Investigators have never before had such powerful tools to study
“autoimmune diseases". It is very likely that in the not too
distant future we will have identified both the seed and soil responsible
for numerous “rheumatic" conditions. Once that is accomplished,
opportunities for effective treatment will rapidly follow. |
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