Autoimmunity & primaryimmunodeficiencyRik Schrijvers MD, PhDAlgemeen interne geneeskundeAllergie en klinische immunologie

Pentalfa 24-01-2019

Introduction

Primary immunodeficiency (PID)• Heterogenous group of inherited disorders with defects in one or more components of the

immune system, characterized by recurrent infections, autoimmunity and/or malignancies.

• Includes >300 disease entities, >300 gene defects:o Severe combined immunodeficiency (SCID)o X-linked agammaglobulinemia (XLA)o Common Variable Immunodeficiency (CVID)o Specific polysaccharide antibody deficiency (SpAD)

• Rare: ~1/10.000 • Most PID patients lack a genetic diagnosis

Bousfiha et al. The 2017 IUIS phenotypic classification for primary immunodeficiencies J Clin Immunol 2018.Photo: The life of "Bubble Boy" David Vetter. Houston Chronicle

Casanova JL. Severe infectious diseases of childhood as monogenic inborn errors of immunity. PNAS 2015. Bomprezzi et al. New approaches to investigating heterogeneity in complex traits. J Med Genet 2003. Grimbacher at al. The crossroads of autoimmunity and immunodeficiency: Lessons from polygenic traits and monogenic defects. J Allergy ClinImmunol 2016. Giudicessi JR et al. Trends in cardiovascular medicine 2018. Okada et al. Genetics of rheumatoid arthritis contribution to biology and drug discovery. Nature 2014

PIDs represent rare (instructive) extremes

• Overlap in monogenic PID-causing genes and risk loci in polygenic systemic autoimmunediseases (15/98 non-MHC genes found in a GWAS for RA in 29,880 patients)

When to think of a PID ?• Any atypical infection, any unusual course

or presentation of typical infection(s).• More than only infection(s):

o Lymphoproliferationo Malignancyo Allergyo Autoimmunity and immunodeficiency

are not mutually exclusive

10 Warning signs - Jeffrey Model Foundation

Autoimmunity is a frequent manifestation in PID• 26.2% (of 2183 PID patients) had autoimmune and/or inflammatory manifestations• Mostly T-cell PIDs and common variable immunodeficiency (CVID)• Autoimmunity is a negative prognostic factor

Fischer et al. Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J Allergy Clin Immunol 2017

Notarangelo et al. Human RAG mutations: biochemistry and clinical implications. Nat Rev Immunol 2016. Theofilopoulos et al. The multiple pathways to autoimmunity. Nat Immunol 2017. Alegre Nat Immunol Rev 2001.

Central

Peripheral

T- and B-cell tolerance

(Selection of) primaryimmunodeficienciesassociated withautoimmunity

• Laboratory resultso IgG 2.02 g/L (-) 7.51-15.60o IgA 0.08 g/L (-) 0.82-4.53o IgM 0.12 g/L (-) 0.46-3.04o Abnormal response to Pneumovax 23o Low switched memory B-cells

Common Variable Immunodeficiency

NLH illustratie, Baden 2016 NEJM

• Case, M36:o 2002 Alopecia areatao 2015 Coincidental finding of liver

test abnormalities: granulomatous hepatitis.

o 2016 onset recidivating RTIo 2017 nodular lymfoid hyperplasia,

corpus dominant gastritis

Common Variable Immunodeficiency• Prevalence 1:25,000• ~21% “CVID”• Diagnosis (ESID-criteria):

o ≥ 1 of the following:• Increased susceptibility to infection• Autoimmune manifestation(s)• Granulomatous disease• Unexplained polyclonal lymphoproliferation• Affected family member with antibody deficiency

o AND IgG (<2.5%) AND low IgA (low/nl IgM) o AND poor response to vaccines and/or low switched memory B cells (< p30)o AND no secondary hypogammaglobulinemia, >4y, no severe T-cell deficiency (≥2 of

following in adults: CD4+ <200, naive CD4 <10%, absent T-cell proliferation)Bonilla et al. International consensus document (ICON): Common variable immunodeficiency disorders. J Allergy Clin Immunol Pract2016. ESID criteria: https://esid.org/Working-Parties/Registry-Working-Party/Diagnosis-criteria

Common Variable Immunodeficiency• Prevalence 1:25,000 • ~21% “CVID”• Diagnosis (ESID-criteria):

o ≥ 1 of the following:• Increased susceptibility to infection• Autoimmune manifestation(s)• Granulomatous disease• Unexplained polyclonal lymphoproliferation• Affected family member with antibody deficiency

o AND IgG (<2.5%) AND low IgA (low/nl IgM) o AND poor response to vaccines and/or low switched memory B cells (< p30)o AND no secondary hypogammaglobulinemia, >4y, no severe T-cell deficiency (≥2 of

following in adults: CD4+ <200, naive CD4 <10%, absent T-cell proliferation)Bonilla et al. International consensus document (ICON): Common variable immunodeficiency disorders. J Allergy Clin Immunol Pract2016. ESID criteria: https://esid.org/Working-Parties/Registry-Working-Party/Diagnosis-criteria

sIgA deficiency

IgA low

IgG lowIgM low

Abnormal response to polysaccharide antigen

vaccination

* In case of low switched memory B-cells** HIGM (hyper IgM syndrome, high IgM)

CVID

SPAD

IgG-deficiency (unspecified antibody

deficiency)

CVID*

XLA

IgG2,3low

Subclass deficiencyMost

monogenic humoral

PIDs (PIK3CD, HIGM**)

Common Variable Immunodeficiency

Gathman et al. Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J Allergy Clin Immunol 2015Resnick et al. Blood 2012

Onset in all age groups Autoimmunity in ~29% Comorbidities are a negative prognostic factor

CVID and autoimmunity• AIHA, ITP,

Neutropenia• Vitiligo, alopecia• Pernicious anemia• AI enteropathy,

hepatitis• Rheumatological

disorders (10% - JIA/RA/JSpA/ undifferentiated inflammatory arthritis)

Farmer et al. Common Variable Immunodeficiency Non-Infectious Disease Endotypes Redefined Using Unbiased Network Clustering in Large Electronic Datasets. Front Immunol. 2018. Azizi et al. Rheumatologic complications in a cohort of 227 patients with common variable immunodeficiency. Scand J Immunol 2018

Tregopathies – role of central tolerance

• Mutations in the gene AIRE lead to insufficient training of T-cellsfor tolerance against self-antigens Clinical features are termed“APECED”o Autoimmunityo PolyEndocrinopathyo Candidiasiso Ectodermal Dysplasia

Cepika et al. J Allergy Clin Immunol 2018. Constantine et al. Lessons from PID: APECED. Immunological reviews 2018. McGovern et al. Oral health in APECED. Eur Arch Paed Dent 2008.

AI-gastritis/hepatitis/vitiligo/…HypoPTH, adrenal insufficiency, T1DAnti-IL17 (CMC)Enamel hypoplasia, nail dystrophy

Tregopathies – role of peripheral T-reg cells• IPEX

o Immunodysregulationo Polyendocrinopathyo Enteropathyo X-linked

• CTLA4 haploinsufficiency• LRBA deficiency• CD25 deficiency

Schmidt et al. Autoimmunity and primary immunodeficiency: two sides of the same coin? Nat Rev Rheumatol 2017Rowshanravan et al. CTLA-4: a moving target in immunotherapy. Blood 2018

Conventional T-cells

RegulatoryT-cells

CTLA4 haploinsufficiencyCTLA4 haploinsufficiency autoimmune infiltration (CHAI) disease

• ANY age of onset• AD, incomplete penetrance• haploinsufficiency of CTLA4 • Clinical manifestations

o Autoimmune cytopenia (ITP 35% AIHA 28%)o Lymphoproliferation (splenomegaly 50%,

lymphadenopathy 28%, GLILD 66%, other organ –brain/kidney/BM infiltration 50%)

o CNS involvemento Enteropathy (IBD, early-onset Crohn) (78%) o Recurrent infectionso Cancer (13%): lymphoma, gastric cancer (EBV)

• Laboratory findingso Declining B-cells, increased CD21lo

o Normal / elevated Tregso Hypogammaglobulinemia (76%)

Kuehn et al. Science 2014. Schubert et al. Nat Med 2014. Zessig et al. 2015 Gut. Cepika et al. J Allergy Clin Immunol 2018. Egg et al. Front Immunol 2018.

Retooling of conventional drugs in PID

• Anti-CTLA4 treatments in cancer: treatment-inducedautoimmunity against tumor antigens, with various off-target autoimmune manifestations

• CTLA-4 treatment (abatacept, Fc-CTLA4) in RA

• CTLA-4 substitution in CTLA-4 haploinsufficiencyRowshanravan et al. CTLA-4: a moving target in immunotherapy. Blood 2018. Lee et al. Abatacept alleviates severe autoimmune symptoms in a patient carrying a de novo variant in CTLA-4. J Allergy Clin Immunol. 2016

JAK-STAT signaling immunodeficiencies• STAT1 gain-of-function

o Recurrent RTIo Bronchiëctasiso Autoimmunity (alopecia

areata, endocrinopathy)o Chronic

mucocutaneouscandidiasis

Schmidt et al. Autoimmunity and primary immunodeficiency: two sides of the same coin? Nat Rev Rheumatol 2017. Grimbacher et al. J Allergy Clin Immunol 2018. Toubiana et al. Blood 2016. Flanagan et al. Nat Genet 2014.

STAT1 GOF

Chronic mucocutaneouscandidiasis

Autoimmunity

STAT3 STAT1 JAK-inhibsruxolitinib

Toubiana et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype; Blood 2015Schmidt et al. Autoimmunity and primary immunodeficiency: two sides of the same coin? Nat Rev Rheumatol 2017

STAT1 GOF

Chronic mucocutaneouscandidiasis Autoimmunity

STAT3 STAT1

+ ruxolitinibHiggins et al. Use of ruxolitinib to successfully treat chronic mucocutaneous candidiasis by gain-of-function signal transducor and activator of transcription 1 (STAT1) mutation. J Allergy Clin Immunol 2015.

PIDs linked with autoimmunity

Schmidt et al. Autoimmunity and primary immunodeficiency: two sides of the same coin? Nat Rev Rheumatol 2018Grimbacher et al. J Allergy Clin Immunol 2016.

Diagnostics and autoimmune serologyin primaryimmunodeficiency

Laboratory diagnostic tools in PID• Immunoglobulin quantification• Functional testing

o Vaccine responses (e.g. Pneumovax23)o LTT, TLR-function, oxidative burst, …

• Flow-cytometric quantifications• Additional testing

o STAT1-fosforylation, auto-antibodies to cytokineso Testing in research context

• DNA sequencing

Hypogammaglobulinemia• Pitfalls

o Hypogammaglobulinemia does not necessarily mean “PID”

2.5% 2.5%

0

Gonzalez‐quintela et al. Levels of immunoglobulins (IgG, IgA, IgM) in a general adult population and their relationship with alcohol consumption, smoking and common metabolic abnormalities. Clinical & Experimental Immunology, 2008, Vol.151(1), pp.42-50

o Serology in immunoglobulin-substitutedpatients reflects endogenous and exogenous immunoglobulins

o Serology is unreliable in absent or poorimmunoglobulin synthesis.

Genetics – next generation sequencing• Reasonable production cost• Interpretation is (very) labor-intensive• Turn-around-time can be long• Only in highly selected patients

Single gene

Panel of genes

(mendeliome)

Whole exomesequencing

Whole genomesequencing

Expression analysisEpigenetics

Conclusions

Conclusions on PID and autoimmunity• PIDs are rare but awareness is essential for the diagnosis• PIDs are instructive for the immunopathogenesis of

autoimmunity• PIDs are frequently accompanied or even preceded by

autoimmunity• PIDs can benefit from retooling of drugs• Low IgG does not necessarily imply a PID diagnosis (but it can)• Lower sensitivity of serological tests in humoral

immunodeficiencies

Questions

Orange et al. 2012 JACI. Schaballie et al. 2017 Front Immunol

• Wat meten we?• Respons op polysaccharidenantigen (Pneumovax23 - Typhim Vi)

• Hoe verloopt dit?

• Frequente vragen:• Mijn patiënt is al gevaccineerd?• Is het zinvol dit te bepalen indien patiënt immunoglobulines krijgt? • Moet ik bij iedereen die ik vaccineer deze labotesten aanvragen?• Mag ik baseline serologie al vroeger afnemen? Quid op moment van (ernstige) ziekte?

Antwoord na polysaccharidenantigen vaccinatie

Pneumovax23Prevenar13

>2maanden

Baseline serologie Respons na 3-4we3 serotypes (8, 9N, 15B, afwezig in Prevenar13, aanwezig in Pneumovax23)

Aanbevelingen HGR : Responsbepaling ikv PID:

. .

LRBA deficiency

• Treatmento Abatacepto Hydroxychloroquine?o Allo HSCT

Gamez-Diaz J Allergy Clin Immunol 2016

Other PIDs linked with autoimmunity• Immune TOR-opathies (gain-of-function in the

PI3K-AKT-mTOR-S6K pathway)