Problemi speciali
Difetti immunitari non convenzionali in pazienti con infezione grave
Non-conventional immune deficiencies in patients with life-threatening infection
Antonio Marzollo1, Jacinta Bustamante2-5, Maria Caterina Putti1, Mauro Stronati6, Matthieu Bendavi7, Jean-Laurent Casanova2-4,7,8, Giuseppe Basso1, Alessandro Borghesi6,9
1UOC di Oncoematologia Pediatrica, Università di Padova; 2St. Giles Laboratory of Human Genetics of Infectious Distasse, Rockefeller Branch, The Rockefeller University, New York, USA; 3Laboratory of Human Genetics of Infectious Distasse, Necker Hospital for Sick Children, Paris, France; 4Paris Descartes University, Imagine Institute, Paris, France: 5Center for the Study of Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris AP-HP, Necker-Enfants Malades Hospital, Paris, France; 6Neonatologia, Patologia Neonatale e Terapia Intensiva, Fondazione IRCCS Policlinico “San Matteo”, Pavia; 7Pediatric Immunology-Hematology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France; 8Howard Hughes Medical Institute, The Rockefeller University, New York, USA; 9Fellay Lab, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Switzerland
Ottobre 2017 - pagg. 503 -510
Abstract
Severe infectious disease in an otherwise healthy child is often perceived as a sporadic
event with no genetic cause. Recent data challenge this assumption showing that a
mutation in genes involved in host defence can be found in a significant proportion of patients.
Some patients may present a classical primary immunodeficiency, either cellular
or humoral; others may have a non-conventional primary immunodeficiency resulting in
an impairment of the immune system predisposing them to a narrow spectrum of infectious
manifestations. Atypical mycobacterial disease and isolated Chronic Mucocutaneous
Candidiasis can be due to defects in IFN-γ or IL-17 respectively. Defects in the production
or response of type I and III interferons can underlie Herpes Simplex encephalitis and severe
Influenza virus infection. The pathogenesis of invasive pyogenic bacteria disease is
more diverse, including complement deficiencies and deficits in the Nuclear Factor kappa
B (NF-kB) pathway. The diagnosis of primary immunodeficiency may have a huge impact
on treatment and prevention of complications for affected patients and their relatives. Moreover,
the dissection of these molecular pathways gives clues about the non-redundant
mechanism of immune defence against a specific infectious agent
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Bibliografia
1. Picard C, Al-Herz W, Bousfiha A, et al. Primary
immunodeficiency diseases: an update
on the classification from the International
Union of Immunological Societies Expert
Committee for Primary Immunodeficiency
2015. J Clin Immunol 2015;35(8):696-726.
2. Casanova J-L, Jouanguy E, Lamhamedi S,
Blanche S, Fischer A. Immunological conditions
of children with BCG disseminated infection.
Lancet 1995;346(8974):581.
3. Caironi M, Badolato R. Il bambino con infezione
da micobatteri non tubercolari. Medico
e Bambino 2015;34(10):634-8.
4. Bustamante J, Boisson-Dupuis S, Abel L,
Casanova J-L. Mendelian susceptibility to mycobacterial
disease: genetic, immunological,
and clinical features of inborn errors of IFN-γ
immunity. Semin Immunol 2014;26(6):454-70.
5. Kreins AY, Ciancanelli MJ, Okada S, et al.
Human TYK2 deficiency: mycobacterial and
viral infections without hyper-IgE syndrome.
J Exp Med 2015;212(10):1641-62.
6. de Beaucoudrey L, Samarina A, Bustamante
J, et al. Revisiting human IL-12Rβ1 deficiency.
Medicine (Baltimore) 2010;89(6):381-402.
7. Guadrini L, Badolato R. La candidiasi mucocutanea
cronica. Medico e Bambino 2013;32
(6):372-6.
8. Puel A, Cypowyj S, Bustamante J, et al. Chronic
mucocutaneous candidiasis in humans
with inborn errors of interleukin-17 immunity.
Science 2011;332(6025):65-8.
9. Lévy R, Okada S, Béziat V, et al. Genetic,
immunological, and clinical features of patients
with bacterial and fungal infections due
to inherited IL-17RA deficiency. Proc Natl
Acad Sci USA 2016:1-9.
10. Puel A, Cypowyj S, Bustamante J, et al. Chronic
mucocutaneous candidiasis in humans
with inborn errors of interleukin-17 immunity.
Science 2011;332(6025):65-8.
11. Ling Y, Cypowyj S, Aytekin C, et al. Inherited
IL-17RC deficiency in patients with chronic
mucocutaneous candidiasis. J Exp Med
2015;212(5):619-31.
12. Boisson B, Wang C, Pedergnana V, et al.
An ACT1 mutation selectively abolishes interleukin-
17 responses in humans with chronic
mucocutaneous candidiasis. Immunity 2013;
39(4):676-86.
13. Zúñiga LA, Jain R, Haines C, Cua DJ. Th17
cell development: from the cradle to the grave.
Immunol Rev 2013;252(1):78-88.
14. Okada S, Markle JG, Deenick EK, et al. Impairment
of immunity to Candida and Mycobacterium
in humans with bi-allelic RORC mutations.
Science 2015;349(6248):606-13.
15. Glocker E-O, Hennigs A, Nabavi M, et al.
A Homozygous CARD9 Mutation in a family
with susceptibility to fungal infections. N Engl
J Med 2009;361(18):1727-35.
16. Lanternier F, Pathan S, Vincent QB, et al.
Deep dermatophytosis and inherited CARD9
deficiency. N Engl J Med 2013;369(18):1704-14.
17. Gaschignard J, Levy C, Chrabieh M, et al.
Invasive pneumococcal disease in children
can reveal a primary immunodeficiency. Clin
Infect Dis 2014;59(2):244-51.
18. Grumach AS, Kirschfink M. Are complement
deficiencies really rare? Overview on
prevalence, clinical importance and modern
diagnostic approach. Mol Immunol 2014;61
(2):110-7.
19. Bolze A, Mahlaoui N, Byun M, et al. Ribosomal
protein SA haploinsufficiency in humans
with isolated congenital asplenia. Science 2013;340(6135):976-8.
20. Picard C, Puel A, Bonnet M, et al.
Pyogenic bacterial infections in humans with
IRAK-4 deficiency. Science 2003;299(5615):
2076-9.
21. von Bernuth H, Picard C, Jin Z, et al. Pyogenic
bacterial infections in humans with
MyD88 deficiency. Science 2008;321(5889):
691-6.
22. Döffinger R, Smahi A, Bessia C, et al. Xlinked
anhidrotic ectodermal dysplasia with immunodeficiency
is caused by impaired NF-kappaB
signaling. Nat Genet 2001;27(3):277-85.
23. Courtois G, Smahi A, Reichenbach J, et al.
A hypermorphic IkappaBalpha mutation is associated
with autosomal dominant anhidrotic
ectodermal dysplasia and T cell immunodeficiency.
J Clin Invest 2003;112(7):1108-15.
24. Pannicke U, Baumann B, Fuchs S, et al.
Deficiency of innate and acquired immunity
caused by an IKBKB mutation. N Engl J Med
2013;369(26):2504-14.
25. Willmann KL, Klaver S, Doğu F, et al. Biallelic
loss-of-function mutation in NIK causes a
primary immunodeficiency with multifaceted
aberrant lymphoid immunity. Nat Commun
2014;5:5360.
26. Boisson B, Laplantine E, Prando C, et al.
Immunodeficiency, autoinflammation and
amylopectinosis in humans with inherited
HOIL-1 and LUBAC deficiency. Nat Immunol
2012;13(12):1178-86.
27. Boisson B, Laplantine E, Dobbs K, et al.
Human HOIP and LUBAC deficiency underlies
autoinflammation, immunodeficiency,
amylopectinosis, and lymphangiectasia. J Exp
Med 2015;212(6):939-51.
28. Picard C, von Bernuth H, Ghandil P, et al.
Clinical features and outcome of patients with
IRAK-4 and MyD88 deficiency. Medicine (Baltimore)
2010;89(6):403-25.
29. Paciolla M, Pescatore A, Conte MI, et al.
Rare mendelian primary immunodeficiency
diseases associated with impaired NF-κB signaling.
Genes Immun 2015;16(4):239-46.
30. Zhou Q, Yu X, Demirkaya E, et al. Biallelic
hypomorphic mutations in a linear deubiquitinase
define otulipenia, an early-onset autoinflammatory
disease. Proc Natl Acad Sci USA
2016;113(36):10127-32.
31. Abel L, Plancoulaine S, Jouanguy E, et al.
Age-dependent mendelian predisposition to
Herpes simplex virus type 1 encephalitis in
childhood. J Pediatr 2010;157(4):623-629.e1.
32. Casrouge A, Zhang S-Y, Eidenschenk C, et
al. Herpes simplex virus encephalitis in human
UNC-93B deficiency. Science 2006;314
(5797):308-12.
33. Zhang S-Y, Jouanguy E, Ugolini S, et al.
TLR3 deficiency in patients with herpes simplex
encephalitis. Science 2007;317(5844):
1522-7.
34. Pérez de Diego R, Sancho-Shimizu V, Lorenzo
L, et al. Human TRAF3 adaptor molecule
deficiency leads to impaired toll-like receptor
3 response and susceptibility to Herpes
simplex encephalitis. Immunity 2010;33(3):
400-11.
35. Sancho-Shimizu V, Pérez de Diego R, Lorenzo
L, et al. Herpes simplex encephalitis in
children with autosomal recessive and dominant
TRIF deficiency. J Clin Invest 2011;
121(12):4889-902.
36. Guo Y, Audry M, Ciancanelli M, et al. Herpes
simplex virus encephalitis in a patient with
complete TLR3 deficiency: TLR3 is otherwise
redundant in protective immunity. J Exp Med
2011;208(10):2083-98.
37. Herman M, Ciancanelli M, Ou Y-H, et al.
Heterozygous TBK1 mutations impair TLR3
immunity and underlie herpes simplex encephalitis
of childhood. J Exp Med 2012;209
(9):1567-82.
38. Andersen LL, Mørk N, Reinert LS, et al.
Functional IRF3 deficiency in a patient with
herpes simplex encephalitis. J Exp Med 2015;
212(9):1371-9.
39. Lim HK, Seppänen M, Hautala T, et al.
TLR3 deficiency in herpes simplex encephalitis:
high allelic heterogeneity and recurrence
risk. Neurology 2014;83(21):1888-97.
40. van de Veerdonk FL, Plantinga TS, Hoischen
A, et al. STAT1 mutations in autosomal
dominant chronic mucocutaneous candidiasis.
N Engl J Med 2011;365(1):54-61.
41. Liu L, Okada S, Kong X-F, et al. Gain-offunction
human STAT1 mutations impair IL-
17 immunity and underlie chronic mucocutaneous
candidiasis. J Exp Med 2011;208
(8):1635-48.
42. Vairo D, Tassone L, Tabellini G, et al.
Severe impairment of IFN-γ and IFN-α responses
in cells of a patient with a novel STAT1 splicing
mutation. Blood 2011;118(7):1806-17.
43. Toubiana J, Okada S, Hiller J, et al. Heterozygous
STAT1 gain-of-function mutations
underlie an unexpectedly broad clinical phenotype.
Blood 2016;127(25):3154-64.
44. Dotta L, Scomodon O, Padoan R, et al. Clinical
and immunological data of nine patients
with chronic mucocutaneous candidiasis disease.
Data Br 2016;7:311-5.
45. Giardino G, Somma D, Cirillo E, et al. Novel
STAT1 gain-of-function mutation and suppurative
infections. Pediatr Allergy Immunol
2016;27(2):220-3.
46. Lafaille FG, Pessach IM, Zhang S-Y, et al.
Impaired intrinsic immunity to HSV-1 in human
iPSC-derived TLR3-deficient CNS cells.
Nature 2012;491(7426):769-73.
47. Paludan SR, Bowie AG, Horan K a, Fitzgerald
K a. Recognition of herpesviruses by the
innate immune system. Nat Rev Immunol
2011;11(2):143-54.
48. Ciancanelli MJ, Huang SXL, Luthra P, et
al. Life-threatening influenza and impaired interferon
amplification in human IRF7 deficiency.
Science 2015;348(6233):448-53.
49. Hubeau M, Ngadjeua F, Puel A, et al. New
mechanism of X-linked anhidrotic ectodermal
dysplasia with immunodeficiency: impairment
of ubiquitin binding despite normal folding of
NEMO protein. Blood 2011;118(4):926-35.
50. Casanova J-L, Conley ME, Seligman SJ,
Abel L, Notarangelo LD. Guidelines for genetic
studies in single patients: lessons from primary
immunodeficiencies. J Exp Med 2014;
211(11):2137-49.
51. Casanova J-L, Abel L. Primary immunodeficiencies:
a field in its infancy. Science 2007;
317(5838):617-9.
Corrispondenza: antonio.marzollo@unipd.it