Elsevier

Neurologic Clinics

Volume 37, Issue 2, May 2019, Pages 219-234
Neurologic Clinics

Genetic Basis of Vasculitides with Neurologic Involvement

https://doi.org/10.1016/j.ncl.2019.01.006Get rights and content

Section snippets

Key points

  • Vasculitides comprise a heterogeneous group of rare diseases with a complex etiology characterized by inflammatory lesions of blood vessels.

  • Some forms of vasculitis are associated with severe neurologic complications that have an impact on the prognosis of the disease.

  • An important progress in the elucidation of the genetic component of vasculitides has occurred during the last decade.

  • Few genetic studies on specific clinical phenotypes of vasculitides have been published due to the difficulty in

Behçet disease

Behçet disease (BD) is a multisystem syndrome with a male preponderance characterized by inflammatory lesions of blood vessels of variable size throughout the body, leading to heterogeneous clinical manifestations. Oral and genital ulceration as well as ocular involvement (mainly uveitis) are the most frequent phenotypes.6 Neurologic complications occur in around 10% to 30% of patients with BD, constituting the so-called neuro-Behçet syndrome (NB), which presents with fever, headache, aseptic

Large vessel vasculitis

Large vessel vasculitides (LVV) are characterized by inflammatory lesions in large-sized vessels such as the aorta, the carotid, and their major branches. This group of vasculitides comprises giant cell arteritis (GCA) and Takayasu arteritis (TAK). Both conditions present a female preponderance, being GCA more frequent in people of European origin over the fifth decade of life and TAK in younger patients with a higher incidence in Asia and Latin America.40, 41

Antineutrophil cytoplasmic antibody-associated vasculitis

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are primary systemic diseases of which major hallmark is a necrotizing inflammation of small blood vessels (arterioles, small arteries, capillaries and, venules) and presence of ANCAs against proteinase 3 (PR3) or myeloperoxidase (MPO). They include granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA, formerly Churg–Strauss syndrome).68

Polyarteritis nodosa

Polyarteritis nodosa (PAN) is a systemic vasculitis affecting mostly medium-sized arteries (generally related to the lungs' circulation but also to other internal organs such as the kidneys). Similar to AAVs, PAN involves necrotizing inflammation of blood vessels, although it is not associated with ANCA production.77 Neurologic manifestations due to ischemia (which leads to thrombosis or bleeding) are relatively common in patients with PAN with an advance disease course. They include headache,

Primary angiitis of the central nervous system

Primary angiitis of the CNS (PACNS), also known as primary CNS vasculitis, is a very rare vasculitis that involves low to medium caliber vessels of the brain, spinal cord, and the meninges, such as leptomeningeal, cortical, and subcortical arteries. The clinical manifestations range from headache to a variety of severe complications of CNS, such as behavioral dysfunction, transient ischemic attacks, or even coma.83

Summary

The use of novel technologies for high-throughput genotyping and, most importantly, the establishment of large collaborative groups, have allowed a substantial increase in the understanding of the genetic network underlying vasculitis predisposition (Table 1). However, because most vasculitides are rare diseases with a complex etiology (in which genetic risk is conferred by hundreds of loci with a low effect independently), only a tiny fraction of their heritability has been unmasked despite

Acknowledgments

FDC was recipient of a grant from the “Ramón y Cajal” program of the Spanish Ministry of Economy and Competitiveness (RYC-2014-16458). RL-M and AM were recipients of a Miguel Servet type I program fellowship from the ISCIII, co-funded by the European Social Fund (ESF, “Investing in your future”) (grants CP16/00033 and CP17/00008, respectively). JM and MAGG were founded by Instituto de Salud Carlos III (ISCIII), Spain, through the RETICS Programs RD16/0012/0004 and RD16/0012/0009 (RIER).

First page preview

First page preview
Click to open first page preview

References (84)

  • M. Kaiser et al.

    Formation of new vasa vasorum in vasculitis. Production of angiogenic cytokines by multinucleated giant cells

    Am J Pathol

    (1999)
  • J.B. Imboden

    Involvement of the peripheral nervous system in polyarteritis nodosa and antineutrophil cytoplasmic antibodies-associated vasculitis

    Rheum Dis Clin North Am

    (2017)
  • J. Graf

    Central nervous system disease in antineutrophil cytoplasmic antibodies-associated vasculitis

    Rheum Dis Clin North Am

    (2017)
  • L. Forbess et al.

    Polyarteritis nodosa

    Rheum Dis Clin North Am

    (2015)
  • R.A. Hajj-Ali et al.

    Diagnosis and classification of central nervous system vasculitis

    J Autoimmun

    (2014)
  • M. Kraemer et al.

    Association of primary central nervous system vasculitis with the presence of specific human leucocyte antigen gene variant

    Clin Neurol Neurosurg

    (2017)
  • J.C. Jennette et al.

    2012 revised International Chapel Hill consensus conference nomenclature of vasculitides

    Arthritis Rheum

    (2013)
  • C.H. Sunderkotter et al.

    Nomenclature of cutaneous vasculitis: dermatologic addendum to the 2012 revised international Chapel Hill consensus conference nomenclature of vasculitides

    Arthritis Rheumatol

    (2018)
  • F.D. Carmona et al.

    Genetics of vasculitis

    Curr Opin Rheumatol

    (2015)
  • G.A. Ramirez et al.

    Intravascular immunity as a key to systemic vasculitis: a work in progress, gaining momentum

    Clin Exp Immunol

    (2014)
  • H. Yazici et al.

    Behcet syndrome: a contemporary view

    Nat Rev Rheumatol

    (2018)
  • D.P. Kidd

    Neurological complications of Behcet's syndrome

    J Neurol

    (2017)
  • Y.J. Lee et al.

    Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behcet's disease

    Ann Rheum Dis

    (2013)
  • N. Mizuki et al.

    Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behcet's disease susceptibility loci

    Nat Genet

    (2010)
  • E.F. Remmers et al.

    Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease

    Nat Genet

    (2010)
  • Y. Kirino et al.

    Genome-wide association analysis identifies new susceptibility loci for Behcet's disease and epistasis between HLA-B*51 and ERAP1

    Nat Genet

    (2013)
  • T. Hughes et al.

    Identification of multiple independent susceptibility loci in the HLA region in Behcet's disease

    Nat Genet

    (2013)
  • L. Ortiz-Fernández et al.

    Genetic analysis with the immunochip platform in Behcet Disease. Identification of residues associated in the HLA class I region and new susceptibility loci

    PLoS One

    (2016)
  • J.H. Kappen et al.

    Genome-wide association study in an admixed case series reveals IL12A as a new candidate in Behcet disease

    PLoS One

    (2015)
  • A. Meguro et al.

    Genetics of Behcet disease inside and outside the MHC

    Ann Rheum Dis

    (2010)
  • Y. Fei et al.

    Identification of novel genetic susceptibility loci for Behcet's disease using a genome-wide association study

    Arthritis Res Ther

    (2009)
  • G.R. Wallace

    HLA-B*51 the primary risk in Behcet disease

    Proc Natl Acad Sci U S A

    (2014)
  • M.J. Ombrello et al.

    Behcet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

    Proc Natl Acad Sci U S A

    (2014)
  • H. Li et al.

    TNFAIP3 gene polymorphisms confer risk for Behcet's disease in a Chinese Han population

    Hum Genet

    (2013)
  • B. Bakir-Gungor et al.

    Identification of possible pathogenic pathways in Behcet's disease using genome-wide association study data from two different populations

    Eur J Hum Genet

    (2015)
  • A. Salmaninejad et al.

    Genetics and immunodysfunction underlying Behcet's disease and immunomodulant treatment approaches

    J Immunotoxicol

    (2017)
  • C. Maldini et al.

    Relationships of HLA-B51 or B5 genotype with Behcet's disease clinical characteristics: systematic review and meta-analyses of observational studies

    Rheumatology (Oxford)

    (2012)
  • D.D. Demirseren et al.

    HLA-B51 subtypes in Turkish patients with Behcet's disease and their correlation with clinical manifestations

    Genet Mol Res

    (2014)
  • M.W. Turner et al.

    Mannose-binding lectin: structure, function, genetics and disease associations

    Rev Immunogenet

    (2000)
  • J. Kim et al.

    Mannose-binding lectin gene-2 polymorphisms and serum mannose-binding lectin levels in Behcet's disease

    Clin Exp Rheumatol

    (2009)
  • Y. Yang et al.

    Genetic polymorphisms of C-type lectin receptors in Behcet's disease in a Chinese Han population

    Sci Rep

    (2017)
  • N. Espinola-Zavaleta et al.

    Altered flow-mediated vasodilatation, low paraoxonase-1 activity, and abnormal high-density lipoprotein subclass distribution in Takayasu's arteritis

    Circ J

    (2009)
  • Disclosure Statement: The authors declare no conflicts of interest related to the subject matter discussed in this review.

    View full text