HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (25) Citing Articles via Google Scholar Google Scholar Articles by Nicolls, M. R. Articles by Voelkel, N. F. Search for Related Content PubMed PubMed Citation Articles by Nicolls, M. R. Articles by Voelkel, N. F.

Autoimmunity and pulmonary hypertension: a perspective

Dept of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA.

CORRESPONDENCE: M. R. Nicolls, Box C272, 4200 E. 9th Ave, UCHSC, Denver, CO 80262, USA. Fax: 1 3033155632. E-mail: mark.nicolls{at}uchsc.edu

Keywords: Auto-antibodies, autoimmunity, endothelium, immune regulation, immune tolerance, pulmonary hypertension

Received: April 15, 2005
Accepted July 12, 2005

	ABSTRACT

TOP ABSTRACT PULMONARY HYPERTENSION:... PAH: AUTOIMMUNITY AND... SCLERODERMA: A PARADIGM OF... AUTOREACTIVE B-CELL ACTIVATION... BONE MORPHOGENETIC PROTEIN... AN INTEGRATED MODEL OF... CONCLUSION REFERENCES

 
The association between autoimmunity and pulmonary arterial hypertension (PAH) has been appreciated for >40 yrs, but how autoimmune injury might contribute to the pathogenesis of this disease has only been examined in a case-specific manner.

It is becoming increasingly clear that a variety of diverse clinical diseases, ranging from viral infections to connective tissue disorders, can culminate in pulmonary vascular pathology that is indistinguishable. Is there a hitherto unappreciated biology that unites these seemingly unrelated conditions?

The answer to this question may come from the increasing body of evidence concerned with the central importance of regulatory T-cells in preventing inappropriate B-cell activity. Two striking similarities between conditions associated with severe angioproliferative pulmonary hypertension are a defect in the CD4 T-cell compartment and auto-antibody production. Pathogenic auto-antibodies targeting endothelial cells are capable of inducing vascular endothelial apoptosis and may initiate the development of PAH.

The present review will focus on what is known about autoimmune phenomena in pulmonary arterial hypertension patients, in order to better consider whether an early loss of self-tolerance followed by autoimmune injury could influence the early development of severe angioproliferative pulmonary hypertension.

Severe pulmonary arterial hypertension (PAH) can be a manifestation of a number of collagen vascular diseases and viral infections. For example, 12% of patients with scleroderma will develop PAH 1. Other disorders, such as systemic lupus erythematosis, polymyositis, Sjögren's syndrome and Hashimo-to's thyroiditis have all been associated with the development of severe PAH 2. It is also known that certain viral infections, e.g. HIV and human herpes virus (HHV)-8, can be associated with the development of severe PAH 3–6. Of great interest, is that all of these conditions are either characterised by, or have a propensity to, autoimmunity. A self-directed immune attack may occur because of a relative paucity of regulatory CD4 cells. It is already known that for some of these diseases, there is a diminution of the putative regulatory subset thought responsible for peripheral immune tolerance, the CD4+CD25+ cell. The present review will discuss how a loss of self-tolerance could initiate a process which ultimately results in PAH.

	PULMONARY HYPERTENSION: PATHOLOGY AND CLASSIFICATION

TOP ABSTRACT PULMONARY HYPERTENSION:... PAH: AUTOIMMUNITY AND... SCLERODERMA: A PARADIGM OF... AUTOREACTIVE B-CELL ACTIVATION... BONE MORPHOGENETIC PROTEIN... AN INTEGRATED MODEL OF... CONCLUSION REFERENCES

 
The most recent clinical and pathological classifications of pulmonary hypertensive diseases were established at the Evian conference 7, and updated in 2003 in Venice, Italy 8. Pathologically, PAH is characterised by a proliferation of endothelial cells and expansion of vascular smooth muscle and adventitial cells in pulmonary arteries 9. There is a growing appreciation that vasoconstriction of pulmonary pre-capillary arterioles may not be the single most important factor leading to severe pulmonary vascular remodelling. Although not yet widely accepted, the authors of the current review use the term "severe angioproliferative pulmonary hypertension" (SAPPH) 10 to distinguish, categorically, between pulmonary vascular disease which develops because of endothelial cell proliferation and pulmonary vascular disease which develops predominantly because of increased muscularisation of vessel walls 8. Examples of PAH arising from endothelial cell pathology include idiopathic pulmonary arterial hypertension (IPAH; formerly known as primary pulmonary hypertension) 8, HIV-induced PAH and CREST (calcinosis, Raynaud's phenomenon, oesophageal dysfunction, sclerodactyly, telangiectasis)-related SAPPH. Examples of PAH associated with severe muscularisation of the pre-capillary arterioles, which demonstrate no clear cut evidence for endothelial cell pathology, include some hypoxia-associated PAH conditions such as chronic mountain sickness 11, 12 and neonatal PAH 13, 14. The term SAPPH is preferred for several reasons. 1) SAPPH provides a pathobiological concept, (i.e. angiogenesis or angioproliferation). 2) SAPPH unites both so-called primary and secondary forms of PAH, under the banner of "severe" and associates the condition with complex pulmonary vascular lesions, including plexiform lesions. 3) SAPPH likely provides prognostic and therapeutic information in that, at the present time, the treatment for these severe forms of angioproliferative PAH is quite similar 10. SAPPH is also characterised by the presence of inflammatory cells in and around affected pulmonary vessels. Heath 15 described the presence of mast cells in plexiform lesions in patients with primary PAH >30 yrs ago. Further work by Tuder et al. 16, and also Humbert et al. 17 described the presence of inflammatory infiltrates in the vascular lesions of PAH. Figures 1 and 2 illustrate the immune pathology in a patient with IPAH which is notable for lymphocyte and mast cell infiltration, as well as immunoglobulin G deposition in and around the narrowed and occluded vascular lumen.

View larger version (132K): [in this window] [in a new window]   Fig. 1— Immune pathology of pulmonary arteriole from an idiopathic pulmonary arterial hypertension patient. A 38-yr-old (antinuclear antibody positive, human herpes virus 8 positive) female expired with idiopathic pulmonary arterial hypertension. a) Haematoxylin and eosin stain showing affected arteriole surrounded by palisading mononuclear cells. b) CD4+ (fast red substrate (red staining); white arrow) and CD8+ (3,3'-diaminobenzidine (brown staining); black arrow) cells around lesion. c) Giemsa stain of mast cells indicating peri-arteriole infiltration. d) A magnified view of the lesion, mast cells are indicated by the black arrows.

View larger version (59K): [in this window] [in a new window]   Fig. 2— Immunoglobulin G staining of plexiform lesion from an idiopathic arterial pulmonary hypertension patient. A 38-yr-old (antinuclear antibody positive) female expired with idiopathic pulmonary arterial hypertension. a) Immunoglobulin G positivity in and around the plexiform lesion (3,3'-diaminobenzidine; brown staining). b) Negative antibody control of peripheral lymph node. c) Positive antibody control of peripheral lymph node.

	PAH: AUTOIMMUNITY AND IMMUNOREGULATION

TOP ABSTRACT PULMONARY HYPERTENSION:... PAH: AUTOIMMUNITY AND... SCLERODERMA: A PARADIGM OF... AUTOREACTIVE B-CELL ACTIVATION... BONE MORPHOGENETIC PROTEIN... AN INTEGRATED MODEL OF... CONCLUSION REFERENCES

The answer to this question may be that most conditions associated with SAPPH are associated with a defect in the CD4 T-cell compartment, meaning that these conditions are either characterised by an absolute deficiency of CD4 cells, a decreased CD4/CD8 ratio and/or a diminished relative percentage of CD4+CD25+ cells, the putative regulatory T-cell (Treg) subset. Specifically, HIV 3, HHV-8 4, 5 and the hepatitis C virus 6, 19–21 are all infections associated with a CD4 defect, autoimmune phenomena (including auto-antibodies) and the development of SAPPH. Similarly, other PAH-associated conditions, including connective tissue disorders, are also associated with a CD4 cell defect. For example, scleroderma 22, 23, systemic lupus erythematosus 24, 25, polymyositis 26, Hashimoto's thyroiditis 27 and Sjögren's Syndrome 28 can all exhibit selective CD4 cell defects and autoimmunity (again including auto-antibodies). More specifically, scleroderma and lupus are associated with a reduction in peripheral CD4+CD25+ cells, the putative Treg population 23–25. Furthermore, PAH has been described following splenectomy 29. Finally, it was recently reported that a patient with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, which is caused by a mutation leading to the loss of function of the autoimmune regulator (AIRE) protein, died with fatal IPAH 30. The AIRE gene is of central importance in the development of thymus-dependent self-tolerance. T-cell, B-cell, macrophage and mast cell infiltration is a characteristic patholological feature of plexiform lesions from SAPPH patients 16, 31. Furthermore, it is estimated that 30–40% of the patients with IPAH are antinuclear antibody positive, and another 10–15% of those patients may express antiphospholipid antibodies 32, 33. A unifying hypothesis that addresses these cumulative findings is that, in the setting of relative or absolute immunodeficiency (which includes diminished Treg activity), immune dysregulation occurs and leads to the activation of pathogenic autoreactive B-cells and T-cells.

If autoimmunity triggers the development of SAPPH, then why is the prevalence of PAH relatively low for certain autoimmune conditions such as systemic lupus erythematosus (6.2%) 34? If the autoimmune phenomena resulting in end-organ damage are at play, why is the pulmonary vasculature not universally involved in these autoimmune connective tissue disorders? While this question can't be answered definitively at this time, there are several possibilities. It is known that in certain autoimmune conditions, a genotype can confer significantly elevated risk without complete disease penetrance. For example, in type 1 diabetes while increased risk is conferred on the basis of the HLA-DR-DQ genotype, fewer than 10% of susceptible individuals or 30–40% of identical twins of a patient with type 1 diabetes will develop the disease 35. Environmental factors such as dietary or viral infections have been invoked as necessary "second hits" to develop this disease. Similarly, it is likely that a two-hit phenomenon may be required such that autoimmunity results in vascular injury and PAH. The current authors hypothesise, that a common factor in PAH-associated conditions is a loss of immunoregulation and that the second "permissive" factor could be the patient's genotype and/or concomitant vascular injury due to infection or temporary high shear stress. In summary, incomplete penetrance of PAH in autoimmune conditions associated with PAH may be due to the requirement of two or more additional factors that are present in a minority of the patients.

	SCLERODERMA: A PARADIGM OF AUTOIMMUNE PAH

TOP ABSTRACT PULMONARY HYPERTENSION:... PAH: AUTOIMMUNITY AND... SCLERODERMA: A PARADIGM OF... AUTOREACTIVE B-CELL ACTIVATION... BONE MORPHOGENETIC PROTEIN... AN INTEGRATED MODEL OF... CONCLUSION REFERENCES

 
Scleroderma is a connective tissue disorder characterised by excessive collagen accumulation in the skin and visceral organs. As mentioned above, it is estimated that 12% of scleroderma patients will develop SAPPH 1. Scleroderma researchers believe that endothelial cell apoptosis may be the first event in the pathogenesis of scleroderma 36. Anti-endothelial antibodies are found in the circulation of scleroderma patients 37, 38, and their presence correlates with the clinical progression of this disease 38. An instigating injury to endothelial cells in scleroderma that may trigger such auto-antibody formation may be viral infection 39. A number of investigators have found evidence for viral infections, such as Epstein-Barr virus, parvovirus B19 and hepatitis C, E, and G in patients with scleroderma 40–45. Although the role of cytomegalovirus (CMV) in the pathogenesis of scleroderma is debated 46, indirect evidence for a role of CMV-specific antibodies in the development of this disease has also been discussed 47, 48. Not only are absolute lymphocyte counts reduced in scleroderma 49, 50, but scleroderma patients also have relatively fewer CD4+CD25+ cells in the peripheral circulation compared with healthy controls 23. In this setting of diminished Tregs, a dysregulation of B-cells is also observed 51. Plexiform lesions found in the arterial walls of scleroderma PAH patients include an inflammatory infiltrate 52 consisting of macrophages, T-cells, B-cells and mast cells 53–55. In summary, scleroderma is an autoimmune disorder that has been associated with viral infection, endothelial damage, diminished Tregs, dysregulated B-cells, abundant mast cells and auto-antibodies. This review will subsequently discuss how Treg activity is related to B-cell activity, how mast cell infiltration is linked to the production of auto-antibodies, and finally, how these processes may culminate in PAH.

	AUTOREACTIVE B-CELL ACTIVATION IN THE ABSENCE OF T-CELL REGULATION

TOP ABSTRACT PULMONARY HYPERTENSION:... PAH: AUTOIMMUNITY AND... SCLERODERMA: A PARADIGM OF... AUTOREACTIVE B-CELL ACTIVATION... BONE MORPHOGENETIC PROTEIN... AN INTEGRATED MODEL OF... CONCLUSION REFERENCES

 
Two findings, made nearly 30 yrs ago, strongly implicated T-cells as being responsible for the control of self-reactive T-cells and B-cells in the maintenance of self-tolerance. In 1969 Nishizuka and Sakakura 56 demonstrated that neonatal thymectomy of normal mice, most notably between day 2 and 4 after birth, led to autoimmune destruction of ovaries. In 1973, Penhale et al. 57 showed that thymectomy of adult rats followed by several exposures to sublethal X-irradiation led to the development of autoimmune thyroiditis. As inoculation of normal CD4+ cells prevented these diseases, both groups suspected that depletion of suppressor T-cells was a putative mechanism for the development of autoimmunity 58, 59. As this population was eventually narrowed down to the CD4+CD25+ cell, it became clear that depletion of this relatively small subpopulation (5–10% of CD4+ cells) was sufficient to break natural self-tolerance and incite chronic and destructive autoimmune diseases. This loss of self-tolerance was associated with the appearance of various disease-specific auto-antibodies 60. With complete elimination of CD4+CD25+ cells, systemic autoimmunity occurs as manifested by multi-organ inflammation and auto-antibody production 61.

In addition to controlling T-cell activity, Tregs influence B-cell responses. For example, CD4+CD25+ Tregs have been shown to directly inhibit lipopolysaccharide-induced proliferation of B-cells in vitro. In an adoptive transfer system, CD4+CD25+ T-cells downregulate T-cell-mediated production of self-reactive antibodies. As activated B-lymphocytes produce CCL5 and attract CD4+CD25+ T-cells in vitro, it has been postulated that B-cell recruitment of CD4+CD25+ T-cells could limit B-cell autoimmune responses 62. CD4+CD25+ cells prevent the activation of anti-DNA antibodies in a transgenic system 63. Thus, Tregs regulate antibody responses against self and nonself antigens. Tregs may exert a direct inhibitory effect on B-cells 62 or may inhibit T-cell differentiation 64. Therefore, in the absence of appropriate regulation by T-cells, auto-antibodies can arise, and autoimmune disease can develop. Thus, a loss of Treg-mediated self-tolerance leads, not only to a loss in T-cell tolerance, but to a breakdown in B-cell tolerance as well. In the absence of these Tregs, other cells presumably provide stimulatory signals to relevant self-reactive B-cells, rescue them from apoptosis, and stimulate them to form pathogenic antibodies 65.

A conventional understanding of autoimmune disorders implicates an inappropriately vigorous T-cell compartment in autoimmune disorders such as diabetes and multiple sclerosis 66. Conversely, autoimmune diseases such as Sjögren's disease and systemic lupus erythematosis, are distinguished by pathogenic auto-antibody production in the setting of apparently compromised Treg function. Autoimmunity in PAH may more closely resemble the latter group of diseases. As discussed above, Treg activity is normally responsible for preventing auto-antibody production. Antibodies directed against the vascular endothelium could certainly promote endothelial apoptosis. It is possible that endothelial apoptosis, secondary to autoimmune injury, could initiate dysfunctional endothelial cell proliferation that culminates in PAH in the same manner that endothelial apoptosis, induced by vascular endothelial growth factor antagonism, results in endothelial cell proliferation and PAH 67. Anti-endothelial antibodies are present in autoimmune disorders associated with PAH including systemic lupus erythematosus 68, mixed connective tissue disease 69 and scleroderma 38. In lupus and Sjögren's syndrome, antibody and complement deposits are localised in the walls of pulmonary arteries of patients with PAH 70, 71. So, in short, the effector cells in this form of autoimmunity may be B-cells which (following differentiation into plasma cells) produce anti-endothelial antibodies. Although the role of autoreactive B-cells is emphasised here, the presence of T-cells in the inflammatory lesion suggests that dysregulated T-cells also contribute to autoimmune injury in PAH.

It is helpful to consider the antiphospholipid syndrome which may be a clinical scenario that has many elements of the PAH model described above. Patients with the antiphospholipid syndrome have altered T-lymphocyte subsets in the periphery, most notably a significantly reduced CD4+CD25+ population 72. The antiphospholipid syndrome is often associated with viral syndromes associated with PAH, such as HIV and hepatitis C, which can have immunomodulatory effects 73. The hypothesis posited here states that defects in the Treg population (which could occur after a viral infection) will lead to a loss of Treg activity with subsequent production of auto-antibodies and associated vascular endothelial injury. The antiphospholipid syndrome is associated with antiphospholipid antibodies that bind and activate endothelial cells. This antibody engagement ultimately leads to apoptosis of vascular endothelial cells 74, 75. Finally, unmanipulated athymic nude mice, that also have an isolated deficiency of T-cells, have been demonstrated to spontaneously develop antiphospholipid antibodies, whereas severe combined immunodeficiency mice, which lack both T- and B-cells, do not have antiphospholipid antibodies 76. Thus, in the antiphospholipid syndrome and other autoimmune disorders, the effector cell of greatest importance may be the dysregulated B-cell that produces auto-antibodies to vascular endothelium because normal regulatory T-cell activity is decreased or absent.

When Treg activity is diminished, mast cells, rather than T-cells, may potentiate B-cell activation via interleukin (IL)-4 (i.e. mast cells may substitute as a source for IL-4 to increase local B-cell activation 77). Of note, mast cells are a significant source of non-T-cell IL-4 78, and IL-4 has been implicated as an expander of autoreactive B-cells 79 and a cytokine of central importance in an experimental model of scleroderma 80–82. The presence of mast cells in and around plexiform lesions has long been observed 15, 31. Mast cells were originally thought to be pathogenically important in PAH 83, and were discounted as it was subsequently demonstrated that a dearth of mast cells did not prevent experimental PAH 84, while a surfeit of mast cells 85, 86 was not associated with clinical PAH. However, mast cells are indeed present in both the inflammatory lesions of PAH patients 31 and monocrotaline-induced PAH in athymic nude rats lacking T-cells 87. The latter group is interesting because monocrotoline-induced PAH is exacerbated by an absence of Tregs (i.e. when no T-cells are present) and is notable for mast cell infiltration in the inflammation around plexiform lesions. The present authors propose that the presence of mast cells may not be required for all subtypes of PAH, but that, as in other autoimmune diseases, mast cells may be an important link between the innate and adaptive immune responses 88, 89. Rather than being absolutely required for the development of PAH, mast cells may be important facilitators of the immune response by potentiating autoreactive B-cells. Given the putative importance of cytokines and chemokines in the generation of an adaptive immune response, it is important to also note that IL-1 and IL-6 serum levels are markedly elevated in severe PAH and may significantly contribute to the inflammatory milieu of this disease 90.

	BONE MORPHOGENETIC PROTEIN RECEPTOR II: A NEW INTERPRETATION OF ITS ROLE IN THE DEVELOPMENT OF PAH

TOP ABSTRACT PULMONARY HYPERTENSION:... PAH: AUTOIMMUNITY AND... SCLERODERMA: A PARADIGM OF... AUTOREACTIVE B-CELL ACTIVATION... BONE MORPHOGENETIC PROTEIN... AN INTEGRATED MODEL OF... CONCLUSION REFERENCES

 
A genetic basis has recently been determined for some cases of familial PAH, i.e. the involvement of germline mutations of bone morphogenetic protein receptor II (BMPR2) 91. BMPR2 is a member of the tumour growth factor (TGF)-ß receptor family and is a ligand for bone morphogenetic proteins (BMPs) 2, 4, 6 and 7, but not TGF-ß 92. Of pertinence to the current model is that BMP2 and -4 have roles in the development, growth potential and apoptosis of T- and B-cells. BMP2 and BMP4 (and likely its receptor, BMPR2) are also essential for thymocyte differentiation 93–95, and proper Treg development in the thymus is critical to avoid autoimmune disease 60. BMP2 mediates growth arrest and apoptosis of B lineage cells 96, 97. Finally, BMP4 is essential for the generation of B-cell progenitors (in addition to erythro-myeloid colony forming cells and natural killer progenitors) 98. It is conceivable that as a receptor for these BMPs, BMPR2 is intimately involved in these immune effects. This has already been suggested for the BMP effects on thymic maturation 93. Thus, it is possible that BMPR2 mutations could deleteriously affect the normal development, maturation, growth arrest and death of lymphocytes. In a manner analogous to patients developing PAH because of AIRE gene mutations 30, germline BMPR2 mutations may, in part, result in PAH because they lead to a fundamental defect in peripheral immune tolerance (i.e. inappropriate Treg development and/or abnormal ability to delete B-cells). This idea opens interesting avenues of research focusing on the role of BMPR2 in immune tolerance rather than simply on its effects on smooth muscle cell growth.

	AN INTEGRATED MODEL OF SAPPH DEVELOPMENT

TOP ABSTRACT PULMONARY HYPERTENSION:... PAH: AUTOIMMUNITY AND... SCLERODERMA: A PARADIGM OF... AUTOREACTIVE B-CELL ACTIVATION... BONE MORPHOGENETIC PROTEIN... AN INTEGRATED MODEL OF... CONCLUSION REFERENCES

 
The fact that PAH generally does not respond to immunosuppression may explain why investigators have not comprehensively explored a causal link between autoimmune injury and PAH. However, it is quite possible that a maladaptive response to an initial inflammatory injury results in a delayed tissue injury response that has a biology entirely distinct from the triggering immune insult and is no longer responsive to immunotherapy, which may have been responsive in the "initiation phase". In the case of PAH, endothelial cell destruction by immune-mediated injury may result in the generation of apoptosis-resistant endothelial cells which share features with malignant cells 99–101. In this scenario, the "law of the monolayer" is broken, and these endothelial cells proliferate, become "heaped up" and eventually obscure the vessel lumen 16. These ideas are represented in figure 3.

View larger version (52K): [in this window] [in a new window]   Fig. 3— A schematic diagram displaying autoimmunity in the evolution of pulmonary arterial hypertension (PAH). 1) Injury to vascular endothelium (e.g. from a vascular trophic virus or shear stress) exposes endothelial antigens. In viral infection, connective tissue diseases or genetic defects in immune tolerance, diminished regulatory T-cell (Treg) activity may be observed. When the "two hits" of vascular injury and diminished peripheral immune tolerance occur simultaneously, this may lead to a loss of the normal control exerted on autoreactive B-cells. As part of the immediate innate host defence to vascular injury, mast cells infiltrate the perivascular space near injured endothelium. Mast cells are a rich source of interleukin (IL)-4, as well as other factors, which are capable of stimulating autoreactive B-cells to secrete auto-antibodies including anti-endothelial cell antibodies. 2) Clinical PAH is characterised by B-cells (B), T-cells (T) and mast cells (M) infiltrating plexiform lesions, and antibody-complement deposits that are located in the pulmonary arteries of patients with PAH. It is possible that during this initial inflammatory period, the lesion could be reversed with immunotherapy. 3) Antibody deposition may contribute to ongoing endothelial apoptosis. 4) As a tissue repair response, ongoing endothelial apoptosis results in the generation of apoptosis-resistant endothelial cells that have a malignant phenotype. This may be a period of injury that is no longer amenable to immunotherapy. 5) Apoptosis-resistant endothelial cells become "heaped-up". The resulting vascular remodelling leads to vascular occlusion, an increased vascular resistance and worsening of PAH.

	CONCLUSION

TOP ABSTRACT PULMONARY HYPERTENSION:... PAH: AUTOIMMUNITY AND... SCLERODERMA: A PARADIGM OF... AUTOREACTIVE B-CELL ACTIVATION... BONE MORPHOGENETIC PROTEIN... AN INTEGRATED MODEL OF... CONCLUSION REFERENCES

In summary, by identifying a critical immune basis for many forms of pulmonary arterial hypertension, a rational design of therapeutic targets for this group of frequently fatal diseases will be strongly facilitated.

	REFERENCES

TOP ABSTRACT PULMONARY HYPERTENSION:... PAH: AUTOIMMUNITY AND... SCLERODERMA: A PARADIGM OF... AUTOREACTIVE B-CELL ACTIVATION... BONE MORPHOGENETIC PROTEIN... AN INTEGRATED MODEL OF... CONCLUSION REFERENCES

 

1. Mukerjee D, St George D, Coleiro B, et al. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis 2003;62:1088–1093.[Abstract/Free Full Text]
2. Fagan KA, Badesch DB. Pulmonary hypertension associated with connective tissue disease. Prog Cardiovasc Dis 2002;45:225–234.[CrossRef][ISI][Medline] [Order article via Infotrieve]
3. Zandman-Goddard G, Shoenfeld Y. HIV and autoimmunity. Autoimmun Rev 2002;1:329–337.[CrossRef][Medline] [Order article via Infotrieve]
4. Parravinci C, Corbellino M, Paulli M, et al. Expression of a virus-derived cytokine, KSHV vIL-6, in HIV-seronegative Castleman's disease. Am J Pathol 1997;151:1517–1522.[Abstract]
5. Kemeny L, Kiss M, Gyulai R, et al. Human herpesvirus 8 in classic Kaposi sarcoma. Acta Microbiol Immunol Hung 1996;43:391–395.[Medline] [Order article via Infotrieve]
6. Onji M, Doi Y, Miyaoka H, Masumoto T, Horiike N, Ohta Y. Serum levels of soluble CD4 and CD8 in patients with chronic viral hepatitis. Hepatogastroenterology 1994;41:377–379.[Medline] [Order article via Infotrieve]
7. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43: Suppl. 12 5S–12S.[Abstract/Free Full Text]
8. Proceedings of the 3rd World Symposium on Pulmonary Arterial Hypertension. Venice, Italy, June 23–25, 2003. J Am Coll Cardiol 2004;43: Suppl. 12 1S–90S.[Free Full Text]
9. Veeraraghavan S, Koss MN, Sharma OP. Pulmonary veno-occlusive disease. Curr Opin Pulm Med 1999;5:310–313.[CrossRef][Medline] [Order article via Infotrieve]
10. Voelkel NF, Cool C. Pathology of pulmonary hypertension. Cardiol Clin 2004;22:343–351.[CrossRef][ISI][Medline] [Order article via Infotrieve]
11. Tucker A, Rhodes J. Role of vascular smooth muscle in the development of high altitude pulmonary hypertension: an interspecies evaluation. High Alt Med Biol 2001;2:173–189.[CrossRef][Medline] [Order article via Infotrieve]
12. Anand IS, Wu T. Syndromes of subacute mountain sickness. High Alt Med Biol 2004;5:156–170.[CrossRef][Medline] [Order article via Infotrieve]
13. Stenmark KR, Orton EC, Reeves JT, et al. Vascular remodeling in neonatal pulmonary hypertension. Role of the smooth muscle cell. Chest 1988;93: Suppl. 3 127S–133S.[Abstract/Free Full Text]
14. Cullinane C, Cox PN, Silver MM. Persistent pulmonary hypertension of the newborn due to alveolar capillary dysplasia. Pediatr Pathol 1992;12:499–514.[ISI][Medline] [Order article via Infotrieve]
15. Heath D. Pulmonary hypertension in pulmonary parenchymal disease. Cardiovasc Clin 1972;4:79–96.[Medline] [Order article via Infotrieve]
16. Tuder RM, Groves B, Badesch DB, Voelkel NF. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol 1994;144:275–285.[Abstract]
17. Humbert M, Morrell NW, Archer SL, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43: Suppl. 12 13S–24S.[Abstract/Free Full Text]
18. Cool CD, Rai PR, Yeager ME, et al. Expression of human herpesvirus 8 in primary pulmonary hypertension. N Engl J Med 2003;349:1113–1122.[Abstract/Free Full Text]
19. Boyer O, Saadoun D, Abriol J, et al. CD4+CD25+ regulatory T-cell deficiency in patients with hepatitis C-mixed cryoglobulinemia vasculitis. Blood 2004;103:3428–3430.[Abstract/Free Full Text]
20. Eddleston AL. Hepatitis C infection and autoimmunity. J Hepatol 1996;24: Suppl. 2 55–60.[ISI][Medline] [Order article via Infotrieve]
21. Panasiuk A, Prokopowicz D, Zak J, Wysocka J. Peripheral blood T, B, and NK cells in relation to histological hepatitis activity and fibrosis stage in chronic hepatitis C. Hepatogastroenterology 2003;50:178–182.[Medline] [Order article via Infotrieve]
22. Degiannis D, Seibold JR, Czarnecki M, Raskova J, Raska K Jr. Soluble and cellular markers of immune activation in patients with systemic sclerosis. Clin Immunol Immunopathol 1990;56:259–270.[CrossRef][ISI][Medline] [Order article via Infotrieve]
23. Ingegnoli F, Trabattoni D, Saresella M, Fantini F, Clerici M. Distinct immune profiles characterize patients with diffuse or limited systemic sclerosis. Clin Immunol 2003;108:21–28.[CrossRef][ISI][Medline] [Order article via Infotrieve]
24. Crispin JC, Martinez A, Alcocer-Varela J. Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun 2003;21:273–276.[CrossRef][ISI][Medline] [Order article via Infotrieve]
25. Liu MF, Wang CR, Fung LL, Wu CR. Decreased CD4+CD25+ T cells in peripheral blood of patients with systemic lupus erythematosus. Scand J Immunol 2004;59:198–202.[CrossRef][ISI][Medline] [Order article via Infotrieve]
26. Benveniste O, Cherin P, Maisonobe T, et al. Severe perturbations of the blood T cell repertoire in polymyositis, but not dermatomyositis patients. J Immunol 2001;167:3521–3529.[Abstract/Free Full Text]
27. Covas MI, Esquerda A, Garcia-Rico A, Mahy N. Peripheral blood T-lymphocyte subsets in autoimmune thyroid disease. J Investig Allergol Clin Immunol 1992;2:131–135.[ISI][Medline] [Order article via Infotrieve]
28. Mandl T, Bredberg A, Jacobsson LT, Manthorpe R, Henriksson G. CD4+ T-lymphocytopenia — a frequent finding in anti-SSA antibody seropositive patients with primary Sjogren's syndrome. J Rheumatol 2004;31:726–728.[ISI][Medline] [Order article via Infotrieve]
29. Hoeper MM, Niedermeyer J, Hoffmeyer F, Flemming P, Fabel H. Pulmonary hypertension after splenectomy? Ann Intern Med 1999;130:506–509.[Abstract/Free Full Text]
30. Korniszewski L, Kurzyna M, Stolarski B, Torbicki A, Smerdel A, Ploski R. Fatal primary pulmonary hypertension in a 30-yr-old female with APECED syndrome. Eur Respir J 2003;22:709–711.[Abstract/Free Full Text]
31. Heath D, Yacoub M. Lung mast cells in plexogenic pulmonary arteriopathy. J Clin Pathol 1991;44:1003–1006.[Abstract/Free Full Text]
32. Yanai-Landau H, Amital H, Bar-Dayan Y, et al. Autoimmune aspects of primary pulmonary hypertension. Pathobiology 1995;63:71–75.[ISI][Medline] [Order article via Infotrieve]
33. Karmochkine M, Cacoub P, Dorent R, et al. High prevalence of antiphospholipid antibodies in precapillary pulmonary hypertension. J Rheumatol 1996;23:286–290.[ISI][Medline] [Order article via Infotrieve]
34. Tanaka E, Harigai M, Tanaka M, Kawaguchi Y, Hara M, Kamatani N. Pulmonary hypertension in systemic lupus erythematosus: evaluation of clinical characteristics and response to immunosuppressive treatment. J Rheumatol 2002;29:282–287.[ISI][Medline] [Order article via Infotrieve]
35. Couper JJ. Environmental triggers of type 1 diabetes. J Paediatr Child Health 2001;37:218–220.[CrossRef][ISI][Medline] [Order article via Infotrieve]
36. Sgonc R, Gruschwitz MS, Dietrich H, Recheis H, Gershwin ME, Wick G. Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. J Clin Invest 1996;98:785–792.[ISI][Medline] [Order article via Infotrieve]
37. Wusirika R, Ferri C, Marin M, et al. The assessment of anti-endothelial cell antibodies in scleroderma-associated pulmonary fibrosis. A study of indirect immunofluorescent and western blot analysis in 49 patients with scleroderma. Am J Clin Pathol 2003;120:596–606.[CrossRef][ISI][Medline] [Order article via Infotrieve]
38. Negi VS, Tripathy NK, Misra R, Nityanand S. Antiendothelial cell antibodies in scleroderma correlate with severe digital ischemia and pulmonary arterial hypertension. J Rheumatol 1998;25:462–466.[ISI][Medline] [Order article via Infotrieve]
39. Vercellotti GM. Effects of viral activation of the vessel wall on inflammation and thrombosis. Blood Coagul Fibrinolysis 1998;9: Suppl. 2 S3–S6.
40. Longo F, Saletta S, Lepore L, Pennesi M. Localized scleroderma after infection with Epstein-Barr virus. Clin Exp Rheumatol 1993;11:681–683.[ISI][Medline] [Order article via Infotrieve]
41. Magro CM, Nuovo G, Ferri C, Crowson AN, Giuggioli D, Sebastiani M. Parvoviral infection of endothelial cells and stromal fibroblasts: a possible pathogenetic role in scleroderma. J Cutan Pathol 2004;31:43–50.[CrossRef][ISI][Medline] [Order article via Infotrieve]
42. Ferri C, Longombardo G, Mugnaini P. Hepatitis E virus and systemic sclerosis. QJM 1998;91:375
43. Ferri C, Zakrzewska K, Longombardo G, et al. Parvovirus B19 infection of bone marrow in systemic sclerosis patients. Clin Exp Rheumatol 1999;17:718–720.[ISI][Medline] [Order article via Infotrieve]
44. Harel L, Straussberg R, Rudich H, Cohen AH, Amir J. Raynaud's phenomenon as a manifestation of parvovirus B19 infection: case reports and review of parvovirus B19 rheumatic and vasculitic syndromes. Clin Infect Dis 2000;30:500–503.[CrossRef][ISI][Medline] [Order article via Infotrieve]
45. Abu-Shakra M, Sukenik S, Buskila D. Systemic sclerosis: another rheumatic disease associated with hepatitis C virus infection. Clin Rheumatol 2000;19:378–380.[CrossRef][ISI][Medline] [Order article via Infotrieve]
46. Hamamdzic D, Kasman LM, LeRoy EC. The role of infectious agents in the pathogenesis of systemic sclerosis. Curr Opin Rheumatol 2002;14:694–698.[CrossRef][ISI][Medline] [Order article via Infotrieve]
47. Neidhart M, Kuchen S, Distler O, et al. Increased serum levels of antibodies against human cytomegalovirus and prevalence of autoantibodies in systemic sclerosis. Arthritis Rheum 1999;42:389–392.[CrossRef][ISI][Medline] [Order article via Infotrieve]
48. Vaughan JH, Shaw PX, Nguyen MD, et al. Evidence of activation of 2 herpesviruses, Epstein-Barr virus and cytomegalovirus, in systemic sclerosis and normal skins. J Rheumatol 2000;27:821–823.[ISI][Medline] [Order article via Infotrieve]
49. Carapeto FJ, Winkelmann RK. Peripheral blood lymphocyte distribution in scleroderma. Dermatologica 1975;151:228–235.[ISI][Medline] [Order article via Infotrieve]
50. Barnett AJ, Tait BD, Barnett MA, Toh BH. T lymphocyte subset abnormalities and HLA antigens in scleroderma (systemic sclerosis). Clin Exp Immunol 1989;76:24–29.[ISI][Medline] [Order article via Infotrieve]
51. Sato S, Fujimoto M, Hasegawa M, Takehara K. Altered blood B lymphocyte homeostasis in systemic sclerosis: expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum 2004;50:1918–1927.[CrossRef][ISI][Medline] [Order article via Infotrieve]
52. Carreira PE. Pulmonary hypertension in autoimmune rheumatic diseases. Autoimmun Rev 2004;3:313–320.[CrossRef][ISI][Medline] [Order article via Infotrieve]
53. Voelkel NF, Tuder RM. Cellular and molecular mechanisms in the pathogenesis of severe pulmonary hypertension. Eur Respir J 1995;8:2129–2138.[Abstract]
54. Harrison NK, Myers AR, Corrin B, et al. Structural features of interstitial lung disease in systemic sclerosis. Am Rev Respir Dis 1991;144:706–713.[ISI][Medline] [Order article via Infotrieve]
55. Dorfmuller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J 2003;22:358–363.[Abstract/Free Full Text]
56. Nishizuka Y, Sakakura T. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 1969;166:753–755.[Abstract/Free Full Text]
57. Penhale WJ, Farmer A, McKenna RP, Irvine WJ. Spontaneous thyroiditis in thymectomized and irradiated Wistar rats. Clin Exp Immunol 1973;15:225–236.[ISI][Medline] [Order article via Infotrieve]
58. Sakaguchi S, Takahashi T, Nishizuka Y. Study on cellular events in postthymectomy autoimmune oophoritis in mice. I. Requirement of Lyt-1 effector cells for oocytes damage after adoptive transfer. J Exp Med 1982;156:1565–576.[Abstract/Free Full Text]
59. Penhale WJ, Irvine WJ, Inglis JR, Farmer A. Thyroiditis in T cell-depleted rats: suppression of the autoallergic response by reconstitution with normal lymphoid cells. Clin Exp Immunol 1976;25:6–16.[ISI][Medline] [Order article via Infotrieve]
60. Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004;22:531–562.[CrossRef][ISI][Medline] [Order article via Infotrieve]
61. Shih FF, Mandik-Nayak L, Wipke BT, Allen PM. Massive thymic deletion results in systemic autoimmunity through elimination of CD4+ CD25+ T regulatory cells. J Exp Med 2004;199:323–335.[Abstract/Free Full Text]
62. Bystry RS, Aluvihare V, Welch KA, Kallikourdis M, Betz AG. B cells and professional APCs recruit regulatory T cells via CCL4. Nat Immunol 2001;2:1126–1132.[CrossRef][ISI][Medline] [Order article via Infotrieve]
63. Seo SJ, Fields ML, Buckler JL, et al. The impact of T helper and T regulatory cells on the regulation of anti-double-stranded DNA B cells. Immunity 2002;16:535–546.[CrossRef][ISI][Medline] [Order article via Infotrieve]
64. Curotto de Lafaille MA, Muriglan S, et al. Hyper immunoglobulin E response in mice with monoclonal populations of B and T lymphocytes. J Exp Med 2001;194:1349–1359.[Abstract/Free Full Text]
65. Tsubata T, Wu J, Honjo T. B-cell apoptosis induced by antigen receptor crosslinking is blocked by a T-cell signal through CD40. Nature 1993;364:645–648.[CrossRef][Medline] [Order article via Infotrieve]
66. Lafaille JJ. The role of helper T cell subsets in autoimmune diseases. Cytokine Growth Factor Rev 1998;9:139–151.[CrossRef][ISI][Medline] [Order article via Infotrieve]
67. Taraseviciene-Stewart L, Kasahara Y, Alger L, et al. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J 2001;15:427–438.[Abstract/Free Full Text]
68. Renaudineau Y, Dugue C, Dueymes M, Youinou P. Antiendothelial cell antibodies in systemic lupus erythematosus. Autoimmun Rev 2002;1:365–372.[CrossRef][Medline] [Order article via Infotrieve]
69. Sasaki N, Kurose A, Inoue H, Sawai T. [A possible role of anti-endothelial cell antibody in the sera of MCTD patients on pulmonary vascular damage relating to pulmonary hypertension]. Ryumachi 2002;42:885–894.[Medline] [Order article via Infotrieve]
70. Quismorio FP Jr, Sharma O, Koss M, et al. Immunopathologic and clinical studies in pulmonary hypertension associated with systemic lupus erythematosus. Semin Arthritis Rheum 1984;13:349–359.[CrossRef][ISI][Medline] [Order article via Infotrieve]
71. Nakagawa N, Osanai S, Ide H, et al. Severe pulmonary hypertension associated with primary Sjogren's syndrome. Intern Med 2003;42:1248–1252.[ISI][Medline] [Order article via Infotrieve]
72. Papo T, Piette JC, Legac E, et al. T lymphocyte subsets in primary antiphospholipid syndrome. J Rheumatol 1994;21:2242–2245.[ISI][Medline] [Order article via Infotrieve]
73. Ramos-Casals M, Cervera R, Lagrutta M, et al. Clinical features related to antiphospholipid syndrome in patients with chronic viral infections (hepatitis C virus/HIV infection): description of 82 cases. Clin Infect Dis 2004;38:1009–1016.[CrossRef][ISI][Medline] [Order article via Infotrieve]
74. Raschi E, Testoni C, Borghi MO, Fineschi S, Meroni PL. Endothelium activation in the anti-phospholipid syndrome. Biomed Pharmacother 2003;57:282–286.[CrossRef][Medline] [Order article via Infotrieve]
75. Riboldi P, Gerosa M, Raschi E, Testoni C, Meroni PL. Endothelium as a target for antiphospholipid antibodies. Immunobiology 2003;207:29–36.[CrossRef][ISI][Medline] [Order article via Infotrieve]
76. Cheng HM, Hu C. Presence of IgG antiphospholipid autoantibody in nude mice. J Rheumatol 1995;22:2006–2007.
77. Karulin AY, Hesse MD, Yip HC, Lehmann PV. Indirect IL-4 pathway in type 1 immunity. J Immunol 2002;168:545–553.[Abstract/Free Full Text]
78. Sherman MA. The role of STAT6 in mast cell IL-4 production. Immunol Rev 2001;179:48–56.[CrossRef][ISI][Medline] [Order article via Infotrieve]
79. Erb KJ, Ruger B, von Brevern M, Ryffel B, Schimpl A, Rivett K. Constitutive expression of interleukin (IL)-4 in vivo causes autoimmune-type disorders in mice. J Exp Med 1997;185:329–339.[Abstract/Free Full Text]
80. Ong C, Wong C, Roberts CR, Teh HS, Jirik FR. Anti-IL-4 treatment prevents dermal collagen deposition in the tight-skin mouse model of scleroderma. Eur J Immunol 1998;28:2619–2629.[CrossRef][ISI][Medline] [Order article via Infotrieve]
81. Ong CJ, Ip S, Teh SJ, et al. A role for T helper 2 cells in mediating skin fibrosis in tight-skin mice. Cell Immunol 1999;196:60–68.[CrossRef][ISI][Medline] [Order article via Infotrieve]
82. Kodera T, McGaha TL, Phelps R, Paul WE, Bona CA. Disrupting the IL-4 gene rescues mice homozygous for the tight-skin mutation from embryonic death and diminishes TGF-beta production by fibroblasts. Proc Natl Acad Sci USA 2002;99:3800–3805.[Abstract/Free Full Text]
83. Tucker A, McMurtry IF, Alexander AF, Reeves JT, Grover RF. Lung mast cell density and distribution in chronically hypoxic animals. J Appl Physiol 1977;42:174–178.[Abstract/Free Full Text]
84. Zhu YJ, Kradin R, Brandstetter RD, Staton G, Moss J, Hales CA. Hypoxic pulmonary hypertension in the mast cell-deficient mouse. J Appl Physiol 1983;54:680–686.[Free Full Text]
85. Voelkel NF, Kruse HP. Disodium cromoglycat for symptomatic therapy of generalized mastocytosis. Inn Med 1977;4:325–330.
86. Castells MC. Mastocytosis: classification, diagnosis, and clinical presentation. Allergy Asthma Proc 2004;25:33–36.[ISI][Medline] [Order article via Infotrieve]
87. Miyata M, Sakuma F, Ito M, Ohira H, Sato Y, Kasukawa R. Athymic nude rats develop severe pulmonary hypertension following monocrotaline administration. Int Arch Allergy Immunol 2000;121:246–252.[CrossRef][ISI][Medline] [Order article via Infotrieve]
88. Benoist C, Mathis D. Mast cells in autoimmune disease. Nature 2002;420:875–878.[CrossRef][Medline] [Order article via Infotrieve]
89. Lee DM, Friend DS, Gurish MF, Benoist C, Mathis D, Brenner MB. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 2002;297:1689–692.[Abstract/Free Full Text]
90. Humbert M, Monti G, Brenot F, et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 1995;151:1628–631.[Abstract]
91. Newman JH, Wheeler L, Lane KB, et al. Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med 2001;345:319–324.[Abstract/Free Full Text]
92. Massague J, Chen YG. Controlling TGF-beta signaling. Genes Dev 2000;14:627–644.[Free Full Text]
93. Hager-Theodorides AL, Outram SV, Shah DK, et al. Bone morphogenetic protein 2/4 signaling regulates early thymocyte differentiation. J Immunol 2002;169:5496–5504.[Abstract/Free Full Text]
94. Graf D, Nethisinghe S, Palmer DB, Fisher AG, Merkenschlager M. The developmentally regulated expression of twisted gastrulation reveals a role for bone morphogenetic proteins in the control of T cell development. J Exp Med 2002;196:163–171.[Abstract/Free Full Text]
95. Tsai PT, Lee RA, Wu H. BMP4 acts upstream of FGF in modulating thymic stroma and regulating thymopoiesis. Blood 2003;102:3947–3953.[Abstract/Free Full Text]
96. Ishisaki A, Yamato K, Hashimoto S, et al. Differential inhibition of Smad6 and Smad7 on bone morphogenetic protein- and activin-mediated growth arrest and apoptosis in B cells. J Biol Chem 1999;274:13637–13642.[Abstract/Free Full Text]
97. Yamato K, Hashimoto S, Imamura T, et al. Activation of the p21(CIP1/WAF1) promoter by bone morphogenetic protein-2 in mouse B lineage cells. Oncogene 2001;20:4383–4392.[CrossRef][ISI][Medline] [Order article via Infotrieve]
98. Nakayama N, Lee J, Chiu L. Vascular endothelial growth factor synergistically enhances bone morphogenetic protein-4-dependent lymphohematopoietic cell generation from embryonic stem cells in vitro. Blood 2000;95:2275–2283.[Abstract/Free Full Text]
99. Tuder RM, Radisavljevic Z, Shroyer KR, Polak JM, Voelkel NF. Monoclonal endothelial cells in appetite suppressant-associated pulmonary hypertension. Am J Respir Crit Care Med 1998;158:1999–2001.[Abstract/Free Full Text]
100. Voelkel NF, Cool C, Lee SD, Wright L, Geraci MW, Tuder RM. Primary pulmonary hypertension between inflammation and cancer. Chest 1998;114: Suppl. 3 225S–230S.[ISI][Medline] [Order article via Infotrieve]
101. Tuder RM, Cool CD, Yeager M, Taraseviciene-Stewart L, Bull TM, Voelkel NF. The pathobiology of pulmonary hypertension. Endothelium. Clin Chest Med 2001;22:405–418.[CrossRef][ISI][Medline] [Order article via Infotrieve]
102. D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115:343–349.
103. Badesch DB, McLaughlin VV, Delcroix M, et al. Prostanoid therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2004;43: Suppl. 12 56S–61S.[Abstract/Free Full Text]
104. Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997;84:223–243.[CrossRef][ISI][Medline] [Order article via Infotrieve]
105. MacGregor AJ, Canavan R, Knight C, et al. Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival. Rheumatology (Oxford) 2001;40:453–459.
106. Sackner MA, Akgun N, Kimbel P, Lewis DH. The pathophysiology of scleroderma involving the heart and respiratory system. Ann Intern Med 1964;60:611–630.
107. Salerni R, Rodnan GP, Leon DF, Shaver JA. Pulmonary hypertension in the CREST syndrome variant of progressive systemic sclerosis (scleroderma). Ann Intern Med 1977;86:394–399.
108. Ungerer RG, Tashkin DP, Furst D, Clements PJ, Gong H Jr, Bein M. Prevalence and clinical correlates of pulmonary arterial hypertension in progressive systemic sclerosis. Am J Med 1983;75:65–74.[ISI][Medline] [Order article via Infotrieve]
109. Wilson L. Cost-of-illness of scleroderma: the case for rare diseases. Semin Arthritis Rheum 1997;27:73–84.[CrossRef][ISI][Medline] [Order article via Infotrieve]
110. Sanchez O, Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary hypertension secondary to connective tissue diseases. Thorax 1999;54:273–277.