cvid a conundrumtotreat 2016... · genetics are helpful in defining the patient‘s diagnosis, but...

CVID a conundrum to treatAn increasing challenge to find the right answers26. November 2016

Klaus Warnatz

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DisclosureCVID in times of NGS

Fudenberg et al Pediatrics 1971

The birth of Common variable immunodeficiencywith an amazing insight

HD CVID

www.ESID.org

Definition of CVIDESID registry criteria 2014

At least one of the following: *increased susceptibility to infection *autoimmune manifestations *granulomatous disease*unexplained polyclonal lymphoproliferation*affected family member with antibody deficiencyAND marked decrease of IgG and marked decrease of IgA with or without low IgM levels (measured at least twice; <2SD of the normal levels for their age);AND at least one of the following:*poor antibody response to vaccines (and/or absent isohaemagglutinins); i.e. absence of protective levels despite vaccination where defined*low switched memory B cells (<70% of age-related normal value)AND secondary causes of hypogammaglobulinaemia have been excluded (see separate list)AND diagnosis is established after the 4th year of life (but symptoms may be present before)AND no evidence of profound T-cell deficiency,

Clinic

Ig serum

AgeExclusion

Specific Ab/ B cell

2° Hypogamma

The conundrum of CVID in 2016

Hypogamma ofUnknown origin

Agamma

sIgAD

CVID

CID

LRBANFkB1...

CSR deficienciesICOS

CD19

Bonilla et al, J Allergy Clin Immunol Pract. 2016; 4:38-59.

PIK3D GOF

Case reportMale CVID patient

History:23y Recurrent sinusitis24y Severe bout of AI hemolytic anemia (AIHA)

Splenomegaly+ lymphadenopathyGLILD

Extensive histology (Lung, LN, BM)Initiation of Steroid Tx

29y bout of AIHA (Hb 5g/dl) after infection start ivIg30y bout of AIHA, first AI thrombocytopenia (AITP)

Giardiasishigh ivIg, steroids, metronidazole

31y stable under steroid treatmentuntil amoeba infection triggers a severe, steroid resistent AITP (0-5G/l!)

Case reportMale CVID patient

History con‘t:31y AITP

Therapy: Romiplostim34y Loss of sensibility from chest down

diagnostics: MRI: longitudinal myelitisCSF: 87 Gpt/l, protein 875 mg/lextensive microbiology: neg.

35y first presentation at the CCI for re-evaluation of ID and Tx-resistent

AITPStart with RTX

2° bout of myelitisvirology/microbiology and Auto Ab neg.

Principles in immunologySelf recognition

Immunological principlesSelf recognition and assessment of danger

Cells of the adaptiveimmune system

(T cell, B cell)

Antigen-presenting cell

Non-Self

Self

Danger signal

SpecificityAssessmentTLR signals

Interferon

Primary antibody deficienciesAssociation with autoimmunity

Primary antibody deficiency Frequency of AI Type of AI

Common variable immunodeficiency >29% AIC, AIE, ILD, a.o.m.

AID deficiency 29% AIC, AIE, AIH, DM, a.o.m

IgG subclass deficiency 28% AIC, AIE etc.

Selective IgA deficiency 25% AIE, SLE, DM, etc

Bruton agammaglobulinemia rare AIE

AI, autoimmunity; AID, activation-induced cytidine deaminase; AIC, autoimmune cytopenia; AIE, autoimmune enteropathy; AIH, autoimmune hepatitis; a.o.m., and other more; DM, diabetes mellitus; ILD, interstitial lung disease; SLE, systemic lupus erythematosus

Durandy et al. Autoimmunity 2013;46:148–56; Gathman et al. JACI 2014;134:116–126; Quartier et al. Clin Immunol 2004;110:22–9; Singh et al. Autoimmun Rev 2014;13:163–177

Autoimmune manifestations in CVIDOverview

249/902 patientsThrombocytopenia 57Hemolytic anemia 23Arthritis 19Vitiligo 17Celiac disease 14Diabetes mellitus 10Crohn-like 7Others...

Gathmann B et al. JACI 2014;134:116–126

Autoimmune cytopenia

Enteropathy

Others

Skin

EndocrinopathyNumbers in bars represent the absolute number of patients per feature (N=902)

15% interstitial lung disease

Autoimmunity in CVIDPathogenic concepts

Antigen receptor recombination

Hypomorphic RAGArtemis

Other SCID genes B and T cell generation is reduced, but not absent.

Homeostatic expansion of T and B cells withreduced repertoire diversity

Altered peripheral control of selectionand expansion of T and B cells

after external trigger

AutoimmunityAutoimmunityOrgan inflammationOrgan inflammationPoor infectioncontrol

Poor infectioncontrol

Schuetz C et al. N Engl J Med 2008;358:2030-8; IJspeert H et al. JACI 2014;133:1124-33 Chen et al. JACI 2014;133:880-2; Lee et al. JACI 2014;133:1099-108; and others

Cuckoo eggsGenetics

Hypomorphic RAG CD21IL2RG reversion BAFF-RArtemisLRBACTLA-4NF-kB 1 and 2STAT1 and 3 GOFADA2RAC2

PI3KdPKCd

CD19TACIICOS?

incomplete

Frontiers of stone?Redefining CID vs CVID in times of NGS

14 · 26. November 2016

Clinical manifestations in CVID

Classical infection profile ofpatient with hypogammaglobulinemia

Unusual infection profile ofpatient with hypogammaglobulinemia!

E Oksenhendler et al DEFI Cohort Clin Infect Dis 2008

Raising suspicion for CID - the cuckoo eggClinic

Infection profile

Which laboratory pieces are required?

IgG low +IgA orIgM low

PoorVaccineResponse 1TD + 1 TI

Boni

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; 29:

4142

-50

CD27 sw mem B cells

CD21 low B cells

naive CD4 T cells

IgG<5

IgA in all?

IgM?

Tet Tox/...

PnPS/...

IgG subclasses Plasmablast response

SmallLympho-cyte panelCD4 / B

LOCIDDefinitions

Bertinchamp et al JACI 2016

Naive CD4 < 10%


T cell activation

Antigen receptor signaling

T cell APC

Described PID with autoimmunityLAT (early onset AI cytopenia)ITK (EBV, progressive hypogammaglobulinemia)PI3K (GOF)STIM1PKC (SLE like phenotype, probably stronger B cell deviation)

Mallisen B et al. Nat Immunol 2014;15:790–7; Rahman A et al. N Engl J Med 2008;358:929–39, Keller et al JEM 2016

CVID B cell signalingReduced NF-kB signal in B cells of 21low patients

Keller et al 2016

And increased CD21low B cells in NF-kB1 deficiency

Signaling in CVID CD21low B cellsSummary

?+ to

Y Baba and T Kurosaki Trends Immunol 2011

Förster et al JI 2010, Keller et al JACI 2016, Keller et al in prep


Regulatory T cells

Low numbers in CVID with AI

Reduced IL-2 (Hel et al. 2014)

Reduced Function (Arandi et al. 2013)

CD

25

FoxP3 CTLA-4

CD

25

Control

CTLA-4+/-

4.4

8.8

1.7

0.8

Haploinsufficiency in CTLA4 (Kuehn et al. 2014)(Schubert et al. 2014)

Arandi et al. Cell Immunol 2013;281:129–33; Hel et al. JoCI 2014;ePub ahead of print; Horn et al. CEI 2009;156:446–54; Kuehn et al. Science 2014;345:1623–7; Schubert et al. Nat Med 2014;ePub ahead of print; Varzaneh et al. JoCI 2014;34:524–43;


Baff levels(Kreuzaler et al. J Immunol 2012)

Lack of Fc inhibition in the absence of IgG(Baerenwaldt et al PNAS 2011)

B cell intrinsic dysregulation

TACI deficiency(Salzer et al. Blood 2009)(Romberg et al. J Clin Invest 2013)

Kreuzaler et al. J Immunol 2012;188:497–503; Romberg et al. J Clin Invest 2013;123:4283–93; Salzer et al. Blood 2009;113:1967–76


Danger signal

Interferon signature(Park et al. PLoS ONE 2013)

Microbial translocation(Perreau et al. JEM 2014)

Microbial IFN induction(Shulzhenko et al. Nat Med 2011)

Park et al. PLoS ONE 2013;8:e74893; Perreau et al. JEM 2014;211:2033–44; Shulzhenko et al. Nat Med 2011;17:1585–93;

- cytotoxicity- tumor rejection- microbe elimination

- Tissue repair- eosinophil recruitment- mucus production- DC migration to lymph

nodes

- formation of secondarylymphoid organs

- B cell activation- macrophage recruitment- epithelium activation and

repair- intestinal barrier

viruses, intracellularbacteria, parasite and fungi

extracellular helminthparasites

Spits et al., February 2013, Nature Reviews Immunology

Immune dysregulation in CVIDInnate lymphocytes (ILC)


Cols et al JACI 2016

Blood HD

BAL

Lymph node

SSC

FSC

SSC

CD45Li

neag

eCD127 CD161 CRTH2 NKp44

CD

56

c-Ki

t

c-Ki

t

CD

127

CD16

ILC2NCR-

ILC3

ILC1

NCR+

ILC3

NCR+

ILC3

CRTH2 NKp44

c-Ki

t

c-Ki

t

CRTH2 NKp44

c-Ki

t

c-Ki

t

Lineage: CD19 (B cells)CD3 (T cells)CD14 (monocytes and macrophages)CD34 (stem cells)FcεRI (mast cells)CD1a (myeloid and plasmacytoid dendritic cells)CD11cCD123BDCA2


HDCVIDcCVIDio HDCVIDcCVIDio HDCVIDcCVIDio

*** ****

****

ILC

sub

sets

cou

nt (c

ells

/ml)

HD

CVIDcCVIDio

****

ILC

cou

nt (c

ells

/ml)

HD

CVIDcCVIDio

0.0

0.1

0.2

0.3

0.4

0.5

HDCVIDcCVIDio HDCVIDcCVIDio HDCVIDcCVIDio

0

20

40

60

80

100

ILC1 ILC2 NCR-ILC3

*** *

• total ILC counts of CVID patients withsecondary clinical complications wereabsolutely decreased

• true for all subsets

• CVID patients suffering only frominfections with reduced absolute ILC3s compared to HD and

• reduced relative ILC3s compared toCVIDc


CVID 5

500µm

CVID 6

Bcl-6

500µm

Bcl-6

r2 = 0.54p = 0.01

controlsCVID>20% CD21low

CVID<20% CD21low

0 10 20 30 40 500

20

40

60

% CD21low of B cells in blood

% il

l-def

ined

GC

s

0

20

40

60 *** ****

% il

l-def

ined

GC

s

S. Unger et al, JoCI 2014

Example of abnormal germinal center differentiationGerminal centers in CVID + lymphoproliferation

Reduced medium survival of CVID patients associated especiallywith ILD, enteropathy (and lymphoma).

Mortality/year since diagnosis of CVID depending on clinical phenotype

brown = no complicationblue = min. one complication

years since diagnosis

H. Chapel et al Blood 2008 + JACI 2012, E Resnick et al Blood 2012

Survival of CVID patientsImpact of secondary manifestations

CVID on the retreatCVID in times of NGS

30 · 26. November 2016

Autoimmune manifestations in CVIDOverview

Autoimmune enteropathyInterstitial lung disease Hepatopathy

CD38

PBL BALPBL

HD CVID Ia patient

CD21

0

2

4

6

8

10

12

CVID-Ia non-Ia DC

pMW = 0.01

Perc

enta

ge o

f B c

ells

(MEA

N)

pKW = 0.019Ia Ib

n= 30 13 Bronchiectasis 14 4Nodules 18 7Lines 23 8Consolidation 15 3Ground glass 17 4

Ground glass was moreprevalent in patients withtype Ia CVID. Pulmonary nodules wereassociated with a higherpercentage of CD21low B lymphocytes.

CD21low B cells in lung tissueChronic inflammatory response

Lung involvement in CVID

Nodular infiltrates

Interstitial lung diseaseManagement: Regular lung function + CO diffusionInitial CT + follow upExclusion of infectious origin (BAL) histology(!?)

Immunosuppressive treatment(steroid, RTX, AZA, CyA, Sirolimus, abatacept..)

Follow up CT + PFT+ sIL2R(?)

Challenges: Role of biopsy? BAL?Indication for IS therapy (!?) First choice steroid sparing agent?Optimal follow upPlace for lung Tx?

http://www.medical-pictures.de/bilder/Anatomie-Leber-(Hepar)-mit-Pfortader-(V-portae)-Pfortadersystem-Pfortaderkreislauf-2514.jpg

Spleen

Liver

Gut

Gastrointestinal tract in CVID

Management: Exclusion of infectious origin (incl Norovirus), histology upper and lower GI, Calprotectin(?)Food Intolerance, HLA DQ2/8 (?) Immunosuppressive treatment if indicated((local) steroids, AZA, CyA, Sirolimus, vedolizumab, anti TNF?), Challenges: Indication for IS (!?), choice of IS

Autoimmuneenteropathy

Nodular regenerative Hyperplasia TIPS for portal hypertension

Therapy: TIPS clear reduction of portal hypertension, no relapse of ascites(Variceal

bleeding, improvement of hypersplenism, but not sufficient long term data

Possibly increased risk of systemic infection

Histology Fr. Prof. A. Schmitt Graeff

Liver involvement in CVID

SummaryDefinitions

Bertinchamp et al JACI 2016

The term CVID is still needed as a clinical diagnosis.

Its frontiers need to be carefully redefined.

The redefined frontiers to hypogamma of unknown significance and especially towards CID need to be carefully tested for each patient.

Genetics are helpful in defining the patient‘s diagnosis, but they are one of three sides of the coin.

We need to improve our pathogenetic diagnostics unveiling underlying common pathogenetic mechansims opening new venues for therapy.

There is a whole story about “More is less“ in CVID and CD21low B cells are right in the middle of this.

4 WORKSHOP onDiagnostics of Immunodeficiencies

th

Endorsed by:19 - 21 June 2017

Freiburg, Germany

For more details see our website:www.uniklinik-freiburg.de/cci/news/events

Prof. Dr. S. Ehl, Prof. B. GrimbacherProf. Dr. Reinhard Voll

AG WarnatzS. Gutenberger B. Keller K. MeloI.Stumpf S. Unger C. LeeAG EibelH. Eibel B. FischerAG Grimbacher Inst. of Pathology UK FrB. Grimbacher M.Seidl, G.Kayser

A. Schmitt-Graeff, M. WernerM. RizziCVID Outpatient:S. Goldacker C. Echternach S.BrassM.Klima M. ErlerImmune Diagnostics:U.Salzer M. Rakhmanov R.DraegerCollaborators: STILPAD consortiumM.van der Burg Rotterdam, M. van ZelmSt. Tangye Sidney, K.BoztugP. Stepensky O. AbuzaitounSponsors: DFG TRR130, DECIDE, DACH, IMPATH

BMBF

TRR130

Acknowledgements

And especially our patients!

cvid a conundrumtotreat 2016... · genetics are helpful in defining the patient‘s diagnosis, but...

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