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La genetj tjca al servizio della clinica nelle immunodefj fjcienze primitj tjve Dr. Boaz Palterer Dipartjmento di Medicina Clinica e Sperimentale Scuola di Specializzazione in Allergologia e Immunologia Clinica Universit degli Studi di

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La genetj tjca al servizio della clinica nelle immunodefj fjcienze primitj tjve

  • Dr. Boaz Palterer

Dipartjmento di Medicina Clinica e Sperimentale Scuola di Specializzazione in Allergologia e Immunologia Clinica Università degli Studi di Firenze

FIRENZE 11 – 12 Novembre 2016

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FIRENZE 11 – 12 Novembre 2016 Pediatrics; May 1971, VOLUME 47 / ISSUE 5

  • H. Fudenberg, R. A. Good, H. C. Goodman, W. Hitzig, H. G. Kunkel, I. M. Roitu, F. S. Rosen, D. S. Rowe, M. Seligmann, J. R. Soothill
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FIRENZE 11 – 12 Novembre 2016

ESID/PAGID 1999, CVID:

  • Decrease of IgG (at least 2 SD below the mean for age) and a marked decrease in at least one of the isotypes IgM or IgA,
  • Onset of immunodeficiency at greater than 2 years of age
  • Absent isohemagglutinins and/or poor response to vaccines
  • Defined causes of hypogammaglobulinemia have been excluded according to a list of differential diagnosis

[…] The number of potential distinct entities within this group is still unknown, and the diagnosis remains one of exclusion. Monogenic forms have been described, but polygenic inheritance is likely in most. Despite the fact that several monogenic defects underlying apparent CVID have been defined, because of the rarity of each defect and the lack in most cases of significant impact on management, as well as the cost of testing, genetic

studies are not considered appropriate for routine use in patients with CVID at this time.

  • Incidence ~ 1:10.000 – 1:100.000
  • Rare disease… but most frequent symptomatjc PID in adults!
  • Mendelian Inheritance ~5-25%
  • However untjll 2012 only rare monogenic forms: ICOS, BAFF-R, CD19, CD20, CD81
  • Some common genetjc factors (TACI/TNFRSF13B and MSH5 polymorphisms)
  • Bimodal peak of incidence (fjrst decade and third decade)
  • Long diagnostjc delay! (~4-10 years)
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Neoplastic Hodgkin and non-Hodgkin Lymphoma Cancer

33-80% ‘’infectjon-only phenotype’’ Vs 20-67% ‘’complicated phenotype’’

Heterogeneous Disease

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FIRENZE 11 – 12 Novembre 2016

Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune defjciency over 4 decades. Blood. 2012;119(7):1650-1657. doi:10.1182/blood-2011-09-377945.

33-80% ‘’infectjon-only phenotype’’ Vs 20-67% ‘’complicated phenotype’’

The importance of being complicated

’70: survival 12 years afuer diagnosis = <30% ’90: survival 20 years afuer diagnosis = 64-67% (vs general populatjon 92-94%)

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The long road to phenotyping

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ESID registry CVID criteria

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2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 5 10 15 20 25 30 35 40 2004; 1 2007; 3 2008; 3 2011; 6

…e la genetica… ?

Identjfjed CVID genes

  • Mutazioni o polimorfjsmi relatjvamente comuni con scarso signifjcato

diagnostjco o prognostjco (TACI)

  • Mutazioni rarissime
  • Ricerca con studi di singole famiglie, mediante geni candidatj, alterazioni

immunologiche evidentj o con studi omozigosità e altri approcci complessi e costosi.

  • Nella pratjca metodiche di sequenziamento ‘’tradizionali’’: lente e costose
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FIRENZE 11 – 12 Novembre 2016

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Sanger sequencing = ~2400$/Mbp NGS Various NGS platgorms = 10 to 0.05$/Mbp

Cost to sequence a human genome estjmate

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Targeted panel VS Whole-exome VS Whole-genome sequencing

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2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 5 10 15 20 25 30 35 40 2004; 1 2007; 3 2008; 3 2011; 6

Identjfjed CVID genes

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FIRENZE 11 – 12 Novembre 2016

Expanding and merging of disease phenotypes CVID

CID SCID LOCID

DCLREC1C / ARTEMIS JAK3 AK2 RAG1 and RAG2

Hum Mol Genet. 2015 Dec 20;24(25):7361-72. doi: 10.1093/hmg/ddv437. Epub 2015 Oct 16. DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency. Volk T1, et al. J Investig Allergol Clin Immunol. 2015;25(3):218-20. Common Variable Immunodeficiency or Late-Onset Combined Immunodeficiency: A New Hypomorphic JAK3 Patient and Review of the Literature. Abolhassani H, Cheraghi T, Rezaei N, Aghamohammadi A, Hammarström L.

A NOVEL MUTATION IN AK2 RESULTS IN COMMON VARIABLE IMMUNODEFICIENCY

  • R. Hoyos et al. Poster ESID6-0116 Barcelona 2016
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RAG defj fjciency

Agammaglobulinemia associated to nasal polyposis due to a hypomorphic RAG1 mutation in a 12 years old boy. Cifaldi C, et al. Clin Immunol. 2016 Oct 3. pii: S1521-6616(16)30410-7. doi: 10.1016/j.clim.2016.09.013. [Epub ahead of print] RAG1 deficiency may present clinically as selective IgA deficiency. Kato T, et al. J Clin Immunol. 2015 Apr;35(3):280-8. doi: 10.1007/s10875-015-0146-4. A hypomorphic recombination-activating gene 1 (RAG1) mutation resulting in a phenotype resembling common variable immunodeficiency. Abolhassani et al. J Allergy Clin Immunol. 2014 Dec;134(6):1375-80. doi: 10.1016/j.jaci.2014.04.042. Omenn syndrome: a disorder of Rag1 and Rag2 genes. Villa A, et. al J Clin Immunol. 1999 Mar;19(2):87-97. Review.

J Clin Immunol. 2016 Oct;36(7):725-32. doi: 10.1007/s10875-016-0326-x. Epub 2016 Aug 18. Unrelated Hematopoietic Cell Transplantation in a Patient with Combined Immunodeficiency with Granulomatous Disease and Autoimmunity Secondary to RAG Deficiency. John T1, et al.

Hypomorphic Rag mutations can cause destructive midline granulomatous disease. De Ravin SS, et al.

  • Blood. 2010 Aug 26;116(8):1263-71. doi: 10.1182/blood-2010-02-267583.
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FIRENZE 11 – 12 Novembre 2016 Kaplan-Meier curves for patients with CVID. (1) Cumulative; (2) without cancers; and (3) with cancer complications. Isabella Quinti et al. Blood 2012;120:1953-1954

Tumors, DNA repair and radiosensitj tjvity

Malignancies are the major cause of death in patjents with adult onset CVID

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  • Immunogenetics. 2011 Jan;63(1):1-11. doi: 10.1007/s00251-010-0483-7. Epub 2010 Oct 12.

Altered spectrum of somatic hypermutation in common variable immunodeficiency disease characteristic of defective repair of mutations. Duvvuri B1, Duvvuri VR, Grigull J, Martin A, Pan-Hammarström Q, Wu GE, Larijani M.

PLoS One. 2010 Aug 18;5(8):e12260. doi: 10.1371/journal.pone.0012260. Unique DNA repair gene variatj tjons and potentj tjal associatj tjons with the primary antj tjbody defj fjciency syndromes IgAD and CVID. Ofger SM1, Pan-Hammarström Q, Hammarström L, Harris RS.

MLH1, MSH2, MSH5, NBS1, RAD50

Tumors, DNA repair and radiosensitj tjvity

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Common variable immunodefj fjciency caused by FANC mutatj tjons

  • Y. Sekinaka et al. Poster ESID6-0818 Barcelona 2016

2 Patjents presentjng with adult onset CVID skewed CD45RO+ memory T-cells, absent TRECs and sjKRECs No anemia, thrombocytopenia or neutropenia WES  FANCA and FANCE mutatjons

Common variable immunodefj fjciency syndrome associated with BRCA2 mutatj tjon

  • R. Romano et al. Poster ESID6-0540 Barcelona 2016

The patjent was born to fjrst-degree consanguineous parents, with history of cancer and mental retardatjon. Diagnosis of CVID was made at 9 years old of age. Moreover, the patjent showed typical symptoms of Fanconi Anemia-like syndrome, such as short stature, mental and developmental delay

Tumors, DNA repair and radiosensitj tjvity

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Tumors, DNA repair and radiosensitj tjvity Implicazioni nella gestj tjone clinica:

  • Uso di radiazioni ionizzantj ?
  • Uso di chemioterapici alchilantj ?

Implicazioni prognostj tjche ed etj tjche:

  • Screening per tumori più stretuo ?
  • Rischio di tumori nella famiglia ?
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J Clin Immunol. 2016 Apr;36(3):179-86. doi: 10.1007/s10875-016-0245-x. Epub 2016 Feb 27. Defj fjciency of Adenosine Deaminase 2 Causes Antj tjbody Defj fjciency. Schepp J1, et al.

Autoinfm fmammatj tjon

N Engl J Med. 2014 Mar 6;370(10):911-20. doi: 10.1056/NEJMoa1307361. Epub 2014 Feb 19. Early-onset stroke and vasculopathy associated with mutatj tjons in ADA2. Zhou Q1, et al.

Defjcency of ADA2

  • Familial Panarteritjs Nodosa
  • Sneddon syndrome
  • Livedo racemosa

17 yo, female SLE-like disease Vasculopathy Splenomegaly 32 yo, male 18yo SIgAD  evolutjon to CVID, No vasculitjs, chronic infmammatory state Splenomegaly, aphtosis, enteropathy

CECR1 (Cat Eye Syndrome Critjcal Region Protein 1 )

Rapid and sustained efg fgect of antj tj-TNF treatment in patj tjents with ADA2 defj fjciency R Caorsi,1 et al. Pediatr Rheumatol Online J. 2015; 13(Suppl 1): O80.

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CTLA-4 and LRBA

Immunedysregulatj tjon, Autoimmunity and Ly Lymphoproliferatj tjon

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CTLA-4 defj fjciency or haploinsuffj ffjciency

Immunedysregulatj tjon, Autoimmunity and Ly Lymphoproliferatj tjon

AD with incomplete penetrance

LRBA defj fjciency

Autosomal recessive

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  • Science. 2015 Jul 24;349(6246):436-40. doi: 10.1126/science.aaa1663.

AUTOIMMUNE DISEASE. Patj tjents with LRBA defj fjciency show CTLA4 loss and immune dysregulatj tjon responsive to abatacept therapy. Lo B1, et al.

Immunedysregulatj tjon, Autoimmunity and Ly Lymphoproliferatj tjon

CTLA-4 and LRBA defj fjciency

JAMA Ophthalmol. 2016 Jul 1;134(7):844-6. doi: 10.1001/jamaophthalmol.2016.1013. Assessment of CTLA-4 Defj fjciency-Related Autoimmune Choroidopathy Response to Abatacept. Shields CL1, et al.

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Immunedysregulatj tjon, Autoimmunity and Ly Lymphoproliferatj tjon

Actj tjvated PI3Kδ Syndrome (APDS)

  • Science. 2013 Nov 15;342(6160):866-71. doi: 10.1126/science.1243292.

Epub 2013 Oct 17. Phosphoinositj tjde 3-kinase δ gene mutatj tjon predisposes to respiratory infectj tjon and airway damage. Angulo I1, et al. J Exp Med. 2014 Dec 15;211(13):2537-47. doi: 10.1084/jem.20141759. Epub 2014 Dec 8. Heterozygous splice mutatj tjon in PIK3R1 causes human immunodefj fjciency with lymphoproliferatj tjon due to dominant actj tjvatj tjon of PI3K. Lucas CL1, et al. PIK3CD J Allergy Clin Immunol. 2016 Jun 29. pii: S0091-6749(16)30350-5. doi: 10.1016/j.jaci.2016.03.055. [Epub ahead of print] Phosphatase and tensin homolog (PTEN) mutatj tjon can cause actj tjvated phosphatj tjdylinositol 3-kinase δ syndrome-like immunodefj fjciency. Tsujita Y1, et al. PTEN

APDS-like APDS1 APDS2

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Immunedysregulatj tjon, Autoimmunity and Ly Lymphoproliferatj tjon

Actj tjvated PI3Kδ Syndrome (APDS)

PTEN

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Immunedysregulatj tjon, Autoimmunity and Ly Lymphoproliferatj tjon

Actj tjvated PI3Kδ Syndrome (APDS)

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Genetjc studies to investjgate monogenic forms of CVID or for disease-modifying polymorphisms are not generally required for diagnosis and management in most of the patjents, especially those who present with infectjons only without immune dysregulatj tjon, autoimmunity, malignancy, or other complicatj

  • tjons. In these

latuer groups of patjents, however, single gene defects may be amenable to specifjc therapies (eg, stem cell therapy) and molecular genetjc diagnosis should be considered when possible.

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FIRENZE 11 – 12 Novembre 2016 Grimbacher et al. CCI Freiburg, Germany

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J Allergy Clin Immunol. 2016 Oct;138(4):957-969. doi: 10.1016/j.jaci.2016.08.003.

Exome and genome sequencing for inborn errors of immunity.

Meyts I, Casanova JL et al. […] Whole-exome sequencing (WES) is presently the most cost-efgectjve approach for research and diagnostjcs, although whole-genome sequencing ofgers several advantages. The scientjfjc or diagnostjc challenge consists in selectjng 1 or 2 candidate variants among thousands of NGS calls. […] Subsequent functjonal validatjon of the disease-causing efgect of the candidate variant is

  • critjcal. Even the most up-to-date dry lab cannot clinch this validatjon without a seasoned wet
  • lab. […] Finding the needle in the haystack takes patjence, prudence, and discernment.
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Riassumendo:

Nei pazientj con CVID con:

  • Esordio precoce e/o familiarità per PID, neoplasie o autoimmunità
  • Complicata da autoimmunità, infjammazione, linfoproliferazione, neoplasie

Il miglior rapporto costo/performance è fornito dal whole exome sequencing

  • Permetue atuualmente la diagnosi in ~20-50% dei pazientj
  • Prevedibile aumento della sensibilità grazie all’approccio unbiased, al contjnuo

riconoscimento di nuove variantj, al miglioramento dei sofuware di analisi (es. CNVs) e dei database di riferimento.

  • Necessaria grande atuenzione nella identjfjcazione delle variantj (coerenza clinica,

Sanger di conferma, studi funzionali) La ricerca di una causa genetjca è raccomandabile in quanto:

  • Può cambiare la diagnosi (CVID mimics)
  • Può cambiare la gestjone clinica (radiosensibilità, screening per tumori)
  • Può cambiare la prognosi (forme con progressione a LOCID)
  • Può cambiare la terapia (HSCT, terapie biologiche mirate)
  • Può fornire informazioni sulla ereditabilità e counseling genetjco per i familiari
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In conclusione….

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In conclusione….

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Vi ringrazio per l’atu tuenzione…

FIRENZE 11 – 12 Novembre 2016

  • Prof. Fabio Almerigogna
  • Dotu. Daniele Cammelli
  • Dotu. Andrea Matucci

Dotu.ssa Alessandra Vultaggio Dr.ssa Maria Grazia Giudizi Dr.ssa Roberta Biagiot

  • Prof. Enrico Maggi

Prof.ssa Paola Parronchi

  • Prof. Francesco Annunziato
  • Prof. Lorenzo Cosmi
  • Prof. Francesco Liotua

Azienda Ospedaliero Universitaria di Careggi SOD Immunologia e Terapie Cellulari SOD Immunoallergologia Gli specializzandi della Scuola di Allergologia e Immunologia Clinica I tecnici del laboratorio di Immunoallergologia

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Autoinfm fmammatj tjon

N Engl J Med. 2012 Jan 26;366(4):330-8. doi: 10.1056/NEJMoa1102140. Epub 2012 Jan 11. Cold urtj tjcaria, immunodefj fjciency, and autoimmunity related to PLCG2 deletj tjons. Ombrello MJ1, et al.

PLCG2-associated Antjbody defjcency and Immune Dysregulatjon

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Immunedysregulatj tjon: Autoimmunity and Lymphoproliferatj tjon

  • Blood. 2015 Jan 22;125(4):591-9. doi: 10.1182/blood-2014-09-602763. Epub 2014 Oct 30.

Early-onset lymphoproliferatj tjon and autoimmunity caused by germline STAT3 gain-of-functj tjon mutatj tjons. Milner JD1, et al.

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Expanding and merging of disease phenotypes CVID

FHL

STXBP2 UNC13D

  • Blood. 2001 Sep 1;98(5):1321-5.

Alterations of the X-linked lymphoproliferative disease gene SH2D1A in common variable immunodeficiency syndrome. Morra M1, et al.

XLP

SH2D1A / SAP BIRC4 / XIAP

Case Rep Med. 2011;2011:121258. doi: 10.1155/2011/121258. Epub 2011 Apr 12. X-Linked Lymphoproliferative Syndrome and Common Variable Immunodeficiency May Not Be Differentiated by SH2D1A and XIAP/BIRC4 Genes Sequence Analysis. Gulez N1, et al.

  • Haematologica. 2010 Dec;95(12):2080-7. doi: 10.3324/haematol.2010.029389. Epub

2010 Sep 7. Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D andSTXBP2 overlaps with primary immunodeficiency diseases. Rohr J1, et al.

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Expanding and merging of disease phenotypes CVID

Other Ab defj fjcencies Agammaglobulinemi a BTK

Clin Exp Immunol. 2001 Jun;124(3):465-9. Assessment of male CVID patj tjents for mutatj tjons in the Btk gene: how many have been misdiagnosed? Weston SA1, Prasad ML, Mullighan CG, Chapel H, Benson EM.

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Delfien J A Bogaert et al. J Med Genet 2016;53:575-590

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Common Variable Immunodefjciency and Circulating TFH

Ana Coraglia,1 Nora Galassi,2 Diego S. Fernández Romero,3 M. Cecilia Juri,3Marta Felippo,2 Alejandro Malbrán,3 and María M. E. de Bracco1,2 Journal of Immunology Research, Volume 2016 (2016), Article ID 4951587, 10 pages

Expansion of infmammatory innate lymphoid cells in patjents with common variable immune defjciency.

Cols M, Rahman A, Maglione PJ, et al. The Journal of allergy and clinical immunology. 2016;137(4):1206-1215.e6. doi:10.1016/j.jaci.2015.09.013.