Manish Butte

Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency.

J Clin Invest. 2015 Oct 12;

Authors: Walter JE, Rosen LB, Csomos K, Rosenberg JM, Mathew D, Keszei M, Ujhazi B, Chen K, Lee YN, Tirosh I, Dobbs K, Al-Herz W, Cowan MJ, Puck J, Bleesing JJ, Grimley MS, Malech H, De Ravin SS, Gennery AR, Abraham RS, Joshi AY, Boyce TG, Butte MJ, Nadeau KC, Balboni I, Sullivan KE, Akhter J, Adeli M, El-Feky RA, El-Ghoneimy DH, Dbaibo G, Wakim R, Azzari C, Palma P, Cancrini C, Capuder K, Condino-Neto A, Costa-Carvalho BT, Oliveira JB, Roifman C, Buchbinder D, Kumanovics A, Franco JL, Niehues T, Schuetz C, Kuijpers T, Yee C, Chou J, Masaad MJ, Geha R, Uzel G, Gelman R, Holland SM, Recher M, Utz PJ, Browne SK, Notarangelo LD

Abstract
Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/autoimmune manifestations (CID-G/AI), produce a broad spectrum of autoantibodies. Neutralizing anti-IFN-α or anti-IFN-ω antibodies were present at detectable levels in patients with CID-G/AI who had a history of severe viral infections. As this autoantibody profile is not observed in a wide range of other primary immunodeficiencies, we hypothesized that recurrent or chronic viral infections may precipitate or aggravate immune dysregulation in RAG-deficient hosts. We repeatedly challenged Rag1S723C/S723C mice, which serve as a model of leaky SCID, with agonists of the virus-recognizing receptors TLR3/MDA5, TLR7/-8, and TLR9 and found that this treatment elicits autoantibody production. Altogether, our data demonstrate that immune dysregulation is an integral aspect of RAG-associated immunodeficiency and indicate that environmental triggers may modulate the phenotypic expression of autoimmune manifestations.

PMID: 26457731 [PubMed – as supplied by publisher]

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BCGitis and BCGosis in children with primary immunodeficiency – imaging characteristics.

Pediatr Radiol. 2015 Oct 10;

Authors: Shrot S, Barkai G, Ben-Shlush A, Soudack M

Abstract
BACKGROUND: When administered to an immune-compromised patient, BCG (Bacille Calmette-Guérin) can cause disseminated and life-threatening infections.
OBJECTIVE: To describe the imaging findings in children with primary immunodeficiency and BCG-related infections.
MATERIALS AND METHODS: We reviewed the imaging findings of children with primary immunodeficiency treated at a children’s hospital during 2012-2014 with localized or disseminated BCG infection. Imaging modalities included US, CT and radiography.
RESULTS: Nine children with primary immunodeficiency had clinical signs of post-vaccination BCGitis; seven of these children showed disseminated disease and two showed only regional lesions with characteristic ipsilateral lymphadenopathy. Overall, lymphadenopathy was the most prevalent feature (n = 8) and characteristically appeared as a ring-enhancing hypodense (CT) or hypoechoic (US) lesion. Visceral involvement with multiple abscesses appeared in the spleen (n = 2), liver (n = 1) and bones (n = 1). All lesions regressed following appropriate anti-tuberculosis treatment.
CONCLUSION: BCG infection needs to be considered in children with typical findings and with suspected primary immunodeficiency.

PMID: 26454840 [PubMed – as supplied by publisher]

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Primary Immunodeficiency Disorders.

Immunol Allergy Clin North Am. 2015 Nov;35(4):ix-x

Authors: Montanaro A

PMID: 26454319 [PubMed – as supplied by publisher]

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Primary Immunodeficiency Masquerading as Allergic Disease.

Immunol Allergy Clin North Am. 2015 Nov;35(4):767-778

Authors: Chan SK, Gelfand EW

Abstract
Primary immune deficiencies (PIDs) are an uncommon heterogeneous group of diseases that result from fundamental defects in the proteins and cells that enable specific immune responses. Common allergic reactions (eczema, allergic rhinitis, asthma, and food allergies) are exaggerated immune responses that may be manifestations of an underlying PID. Early diagnosis and treatment has significant bearing on outcome. Immune suppression with systemic corticosteroids in these immune compromised individuals can lead to life threatening dissemination of infections.

PMID: 26454318 [PubMed – as supplied by publisher]

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Pulmonary Manifestations of Primary Immunodeficiency Disorders.

Immunol Allergy Clin North Am. 2015 Nov;35(4):753-766

Authors: Nonas S

Abstract
Pulmonary disease, ranging from infectious pneumonia, lung abscess, and empyema to structural lung diseases to malignancy, significantly increase morbidity and mortality in primary immune deficiency. Treatment with supplemental immunoglobulin (intravenous or subcutaneous) and antimicrobials is beneficial in reducing infections but are largely ineffective in preventing noninfectious complications, including interstitial lung disease, malignancy, and autoimmune disease. A low threshold for suspecting pulmonary complications is necessary for the early diagnosis of pulmonary involvement in primary immunodeficiency disorders, before irreversible damage is done, to improve patient outcomes.

PMID: 26454317 [PubMed – as supplied by publisher]

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Autoimmune Disease in Primary Immunodeficiency: At the Crossroads of Anti-Infective Immunity and Self-Tolerance.

Immunol Allergy Clin North Am. 2015 Nov;35(4):731-752

Authors: Saifi M, Wysocki CA

Abstract
The association of autoimmunity and primary immunodeficiency suggests the existence of mechanistic links between development of the various elements of the immune system and the maintenance of self-tolerance. In this review, various monogenic primary immunodeficiencies (PID) are systematically explored, with a specific focus on the impact of these genetic lesions on tolerance, correlating these defects in tolerance with clinical autoimmune and inflammatory syndromes seen in these PIDs. Common variable immunodeficiency (CVID) is explored, and areas are highlighted in which findings in monogenic PID are beginning to illuminate the mechanisms behind these conditions in CVID.

PMID: 26454316 [PubMed – as supplied by publisher]

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Immunoglobulin Replacement Therapy for Primary Immunodeficiency.

Immunol Allergy Clin North Am. 2015 Nov;35(4):713-730

Authors: Sriaroon P, Ballow M

Abstract
Immunoglobulin replacement therapy has been standard treatment in patients with primary immunodeficiency diseases for the past 3 decades. The goal of therapy is to reduce serious bacterial infections in individuals with antibody function defects. Approximately one-third of patients receiving intravenous immunoglobulin treatment experience adverse reactions. Recent advances in manufacturing processes have resulted in products that are safer and better tolerated. Self-infusion by the subcutaneous route has become popular and resulted in better quality of life. This review summarizes the use of immunoglobulin therapy in primary immunodeficiency diseases including its properties, dosing, adverse effects, and different routes of administration.

PMID: 26454315 [PubMed – as supplied by publisher]

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Hematopoietic Stem Cell Transplant for Immune Deficiency and Immune Dysregulation Disorders.

Immunol Allergy Clin North Am. 2015 Nov;35(4):695-711

Authors: Hagin D, Burroughs L, Torgerson TR

Abstract
Primary immunodeficiency disorders were among the first diseases in which hematopoietic stem cell transplant (HSCT) was attempted. Initial attempts at HSCT were discouraging and fraught with complications, but with increased knowledge and sophistication of HLA typing and donor matching, development of improved transplant conditioning regimens, and advances in prophylaxis and treatment of graft-versus-host disease, there has been a marked improvement in outcomes. This improvement has allowed an ever-growing number of different immunodeficiency and immune dysregulation disorders to be treated by HSCT. This article provides an overview of the approach to HSCT in these disorders.

PMID: 26454314 [PubMed – as supplied by publisher]

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Common Variable Immunodeficiency: Diagnosis, Management, and Treatment.

Immunol Allergy Clin North Am. 2015 Nov;35(4):637-658

Authors: Abbott JK, Gelfand EW

Abstract
Common variable immunodeficiency (CVID) refers to a grouping of antibody deficiencies that lack a more specific genetic or phenotypic classification. It is the immunodeficiency classification with the greatest number of constituents, likely because of the numerous ways in which antibody production can be impaired and the frequency in which antibody production becomes impaired in human beings. CVID comprises a heterogeneous group of rare diseases. Consequently, CVID presents a significant challenge for researchers and clinicians. Despite these difficulties, both our understanding of and ability to manage this grouping of complex immune diseases has advanced significantly over the past 60 years.

PMID: 26454311 [PubMed – as supplied by publisher]

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Overview of Immunodeficiency Disorders.

Immunol Allergy Clin North Am. 2015 Nov;35(4):599-623

Authors: Raje N, Dinakar C

Abstract
The spectrum of primary immunodeficiency disorders (PIDs) is expanding. It includes typical disorders that primarily present with defective immunity as well as disorders that predominantly involve other systems and show few features of impaired immunity. The rapidly growing list of new immunodeficiency disorders and treatment modalities makes it imperative for providers to stay abreast of the latest and best management strategies. This article presents a brief overview of recent clinical advances in PIDs.

PMID: 26454309 [PubMed – as supplied by publisher]

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