Recurrent Infection, Pulmonary Disease, and Autoimmunity as Manifestations of Immune Deficiency Presenter of Erwin W. ReproductionGelfand, M.D. Professor, Departmentfor of Pediatrics PropertyNational Jewish Health Professor ofNot Immunology and Pediatrics University of Colorado School of Medicine Disclosures

• Investigator: Boehringer Ingelheim

Presenter of Reproduction for Property Not Learning Objectives

• To understand the interplay between immunodeficiency and allergic and pulmonary disorders. Presenter • To recognize the increasingof numbers of monoallelic immune systemReproduction that have allergic and pulmonaryfor manifestations. • To incorporateProperty genetic testing in the clinical Not evaluation of patients with seemingly common diseases. Hypogammaglobulinemia Autoimmunity (Immunodeficiency) Presenter of Reproduction for Property Not Hypersensitivity Host Defense

Specific Non-Specific Presenter of • Adaptive immunity • Innate immunity Reproduction • Barriers for Property Not The Innate and Adaptive Immune Response

Specific antigen receptors

Presenter of Reproduction for Property Pattern Not recognition receptors

Dranoff G. Nature Reviews Cancer 2004;4:11-22. Primary Immunodeficiency Diseases

Infection Autoimmunity Presenter Atopy Malignancy of Reproduction for Property Not Primary Immunodeficiency Diseases

Infection Autoimmunity Malignancy Presenter of Deficient/defective Deficient/defective effector cells Reproductionregulatory cells for Property Not Primary Immunodeficiency Diseases

Infection Autoimmunity Atopy Malignancy Presenter of Deficient/defective Deficient/defective effector cells regulatoryReproduction cells for Property Not Receptor Signaling

Signal

StrongWeak Absent Presenter of Adaptive IR Atopy Immunodeficiency Reproduction for Th17 Th1 Property Th2 Not

Neutrophilia IFN IgE T Cell Receptor Signaling

Signal

StrongWeak Absent Presenter of Adaptive IR Atopy Immunodeficiency Reproduction for Th17 Th1 Property Th2 Not Autoimmunity Neutrophilia IFN IgE Eosinophilia Pulmonary Complications Associated with PID • Infectious – Bacterial – Fungal Viral – Opportunistic Presenter of • Non-infectious Reproduction – Allergy for Property – AutoimmunityNot – Interstitial lung disease (ILD) • Granulomatous-lymphocytic ILD (GLILD) Sinopulmonary Signs Suggesting an Immune Defect

Presenter of Reproduction for Property Not

Busse PJ, et al. Ann. Allergy Immunol. 98:1-9, 2007 Presenter of Reproduction for Property Not Immunodeficiency Allergy

Presenter of Reproduction for Pulmonary Property Not Immunodeficiency Diseases with Eosinophilia Elevated Serum IgE and Eczema - The Triad –

– Hyper-IgE syndrome (HIES) Presenter of – deficiency Reproduction for Property Not Immunodeficiency Diseases with Eosinophilia Elevated Serum IgE and Eczema - The Triad – and lung disease

– Hyper-IgE syndrome (HIES) Presenter of – DOCK8 deficiency Reproduction for Property Not A Classification of HIES

HIES Inheritance Molecular Genetic Testing Type Type 1 •Sporadic (more • STAT3 mutations than 90% of cases) Presenter •Familial with of autosomal dominant Reproduction inheritance (rare) for Type 2 •Familial withProperty • TYK2 deficiency autosomal Not recessive inheritance •Rare Hyper-IgE (HIES) Syndrome (Job’s Syndrome)

Triad: Cold , , high IgE

• Chronic eczema-like rash/atopic – Onset - newborn rash Presenter – Staphylococcal superinfectionof • High IgE - often >2,000 IU/mL Reproduction • Eosinophilia - usually >700 cells/mL for Property *Generally free fromNot other allergic manifestations (rhinitis, asthma, urticaria, anaphylaxis). Allergic skin testing usually negative Hyper-IgE (HIES) Syndrome (Job Syndrome)

• Characteristic facial appearance-coarse features, prominent forehead, broad nasal bridge • Distinct abnormalities of the connective tissue, skeleton, dentition Presenter • Pneumonia, pneumatocelesof • Mucocutaneous • Coronary and CNS arteryReproduction aneurysms for • Fractures Property • Retained primaryNot teeth • Scoliosis • Joint hyperextensibility Presenter of Reproduction for Property Not Presenter of Reproduction for Property Not Chest Radiograph Showing Right Lower Lobe Infiltrate With Cystic Lesions (Arrow)

Presenter of Reproduction for Property Not

Venkata C et al. Chest 2008;133:1026-1029 Chest CT Scan Showing Extensive Consolidation and Cystic Changes in the Right Lung With Right Pleural Thickening and Left Pleural Effusion With Compressive Atelectasis and Early Infiltrates in the Left Lower Lobe

Presenter of Reproduction for Property Not

Venkata C et al. Chest 2008;133:1026-1029 Immunodeficiency Diseases with Eosinophilia and Elevated Serum IgE

– Hyper IgE syndrome Presenter(HIES) AD-HIES of Reproduction – DOCK8 deficiency AR-HIES for Property Not Combined Immunodeficiency Associated With DOCK8 Mutations

• Severe atopy – Atopic dermatitis – High IgE levels – Moderate eosinophilia – Food sensitivities Presenter • of • Reproduction • Pneumonia for • Recurrent staphylococcalProperty skin infections with otitis externa • Recurrent H. simplex/H.Not zoster • Molluscum • Low T, B, and NK cell numbers • CNS vasculitis* Clinical Features of DOCK8 Deficiency

Atopic dermatitis 91% Asthma 41% 66% High serum IgE Presenter 100% Eosinophilia of 90% Bacterial skin infections 78% Mucocutaneous candidiasisReproduction 72% Any viral infection-HSV,HPV,VZV,for MCV 88% Respiratory tractProperty infections 97% CNS vasculitis Not 6% Malignancy 19% Autoimmune hemolytic anemia 6% Common Variable Immunodeficiency Disease (CVID) Clinical Manifestations of CVID

Infectious Manifestations Noninfectious Manifestations •Pneumonia (atypical and Autoimmune cytopenias typical organisms) GranulomatousPresenterdisease •Otitis media •Lymphadenopathyof •Sinusitis •Splenomegaly •Conjunctivitis •EnteropathyReproduction •Enteritis •forNodular regenerative hyperplasia Property •Polyarthritis Not •Interstitial lung disease/GLILD •Malignancy (lymphoma/MALToma) Clinical and Laboratory Criteria for Diagnosis of CVID Clinical criteria for a probable diagnosis At least one of the following: • Increased susceptibility to infection • Autoimmune manifestations • Granulomatous disease • Unexplained polyclonal lymphoproliferationPresenter • Affected family member with antibody deficiency of Laboratory criteria for a probable diagnosis - Marked decrease of IgG and markedReproduction decrease of IgA with or without low IgM levels (measured at least twice;for <2SD of the age-normal levels AND at least one of the following:Property •Poor antibody response to vaccinesNot (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) GLILD

• Lymphocytic interstitial pneumonia (LIP)

• Follicular bronchiolitisPresenter of • Granulomatous lung diseaseReproduction for Property • Organizing pneumonia Not Silent Radiological Features of GLILD

• Plain X-ray – Diffuse interstitial infiltrates Presenter of • HRCT – Consolidation Reproduction for – Ground glassProperty opacities – Reticular abnormalitiesNot Imaging in Common Variable Immunodeficiency

Presenter of Reproduction for Property Not

• Most common radiologic abnormality in CVID (25-73%), usually in lower lobes • Associated with mucous plugging Presenter and tree-in-bud nodules of • Bronchiectasis is related to history of recurrent infections Reproduction • Bronchiectasis is rare in young for patients. Prevalence Propertyincreases over time, correlating to number of infections Not • However, presence of bronchiectasis does not correlate with IgG levels Granulomatous Lymphocytic Interstitial Lung Disease (GLILD)

• GLILD is a unique Pathology entity, occurring only in •Non-necrotizing the setting of CVID and Presentergranulomas of CVID-like illnesses •LIP • Mixed Reproduction•FB restrictive/obstructive for •Lymphocyte hyperplasia physiology Property •MALToma • Associated with aNot poorer prognosis than CVID without GLILD

Bates CA, et al. J. Allergy Clin. Immunol. 114:415-421, 2004 GLILD - Pathology

Presenter of Reproduction for Property Not Nodular dense lymphoid Non-necrotizing granuloma hyperplasia. Underlying architecture is preserved. GLILD - Radiology

• Characterized uniquely by a combination of ground glass and consolidative opacities with septal thickening, nodularity, and Presenter adenopathy of • Usually lower lung predominant, often peribronchovascular in Reproduction distribution for Property • May progress to fibrosis Not • Radiologic findings may wax and wane over time Lymphoproliferative Disease in CVID

• Increased risk of lymphoma up to 30x

• Most commonly non-Hodgkin lymphoma, B-cell subtype Presenter of • Often extra-nodal and associated with mucosal tissues Reproduction for • MALT (mucosa-associatedProperty lymphoid tissue) lymphomaNot or MALToma, a subset of B-cell non-Hodgkin lymphoma Lymphocytic infiltration in pulmonary MALToma effaces the normal architecture, destroying the bronchiole (arrows) Presenter of Reproduction for Property Not

Maglione PJ, et al. J. Allergy Clin. Immunol. Pract. 3:941-950, 2015 Comparison of Initial Clinical and Laboratory Characteristics

Presenter of Reproduction for Property Not

Maglione PJ, et al. J. Allergy Clin. Immunol. Pract. 3:941-950, 2015 Univariate Analyses of Granulomatous Lymphocytic Interstitial Lung Diseae Predictors

Presenter of Reproduction for Property Not

Mannina A, et al. Ann. Am. Thorac. Soc. 13;1042-1049, 2016 Treatment Options in GLILD

• IVIG • Corticosteroids Presenter • Azathioprine of • Rituximab Reproduction • Mycophenolate for • TNF antagonistsProperty • Cyclosporine Not Granulomatous (non-necrotizing) Disease

• T cells

• B cells Presenter • Follicles with germinal centersof Reproduction for Property Not Presenter of Reproduction for Property Not

Hsu AP, et al. Current Opin. Allergy Clin. Immunol. 15:104-109, 2015 Presenter of Reproduction for Property Not

Spinner MA, et al. Blood 123:809-821, 2014 Mendelian Immune Disorders Predisposing to Mycobacterial Disease

Condition Clinical Form/Molecular Basis Mycobacterium sp MSMD Response to IFN abolished: BCG c-AR-IFN-R1 deficiency M. avium, kansasii c-AR-IFN-R2 deficiency PresenterM. szulzai, chelonae, fortuitum, of abscessus, smegmatis, peregrinum Impaired response to IFN BCG p-AR-IFN-R1 deficiencyReproductionM. avium, kansasii p-AD-IFN-R1 deficiencyfor M. chelonae, abscessus p-AR-IFNProperty-R2 deficiency M. gorvonac, asiaticum p-AD-STAT1 Notdeficiency M. tuberculosis Impaired IFN production: BCG c-AR-IL-12R1 deficiency M. avium, chelonae c-AR-IL-12p40 deficiency M. tuberculosis Presenter of Reproduction for Property Not

Casanova, J.L. et al., Nature Rev. Immunol. 4:55-66, 2004. Presenter of Reproduction for Property Not

Bustamante J, et al. Sem. Immunol. 26:454-470, 2014 Presenter of Reproduction for Property Not

Bustamante J, et al. Sem. Immunol. 26:454-470, 2014 Presenter of Reproduction for Property Not

Bustamante J, et al. Sem. Immunol. 26:454-470, 2014 Presenter of Reproduction for Property Not

Bustamante J, et al. Sem. Immunol. 26:454-470, 2014 Anticytokine AAbs and Disease Associations

Presenter of Reproduction for Property Not

Knight V, et al. Antibodies 5:3, 2016 Monogenic Defects Presenting With Antibody Deficiency, Autoimmunity, and Pulmonary Manifestations

Antibody Gene Product Deficiency Autoimmunity Pulmonary Thymic Selection/Tregs Presenter CTLA4 B-cell defects + LIP of LRBA + + Bronchiectasis/EBV-LIP Signaling Pathways Reproduction ITK + + Nodules for NF-B Signaling Property NF-B1 Not++ Fibrosis STAT Signaling STAT3 GOF + + Mycobacteria TAC1 + + GLILD Immunodeficiency Allergy

Presenter of Reproduction for Pulmonary Property Not