A History of Pediatric Immunology

Immunology has played a prominent role in the history of medicine. Pediatric immunologists have focused on immune aberrations in pediatric disorders, particularly those involving host defense mechanisms. These efforts have paid rich dividends in terms of fundamental knowledge of the immune system and major therapeutic advances, including 1) i.v. immunoglobulin therapy, 2) hematopoietic stem cell transplantation, and 3) gene therapy. Pediatric immunology as an organized discipline emerged in the early 1950s, when pediatricians and their basic scientist colleagues began to focus on clinical and basic research related to immunodeficiency. Since then, key organizations and infrastructure have been developed to support this research and the clinical care of immunodeficient patients. We review here the evolution of contemporary pediatric immunology, particularly in North America, from its roots in 19th-century Europe to its current expression as one of the fundamental scientific and clinical disciplines of pediatrics. Immunology touches every pediatric subspecialty. Most closely aligned to allergy and rheumatology, immunology also has close ties to infectious diseases, hematology, and nephrology. Furthermore, each other specialty has its autoimmune diseases, relies on immunologic tests for diagnosis, and uses immunosuppressive drugs or i.v. immunoglobulin (IVIG) treatment; yet there are only a handful of patients, those with a primary immunodeficiency, to whom no other specialist lays claim. Because these patients are fairly rare, a practicing pediatrician who devoted his practice to primary immunodeficiency would probably starve. Furthermore, no separate board for pediatric immunology exists, although the American Board of Allergy and Immunology, while emphasizing allergy, now has considerable emphasis on clinical immunology and immunodeficiency. This article details the scientific advances as well as the individuals and the organizations involved in the development of the specialty of pediatric immunology. FOUNDATIONS OF PEDIATRIC IMMUNOLOGY Variolation and vaccination. Conventional wisdom traces the birth of immunology to 1798, when Edward Jenner (1749 -1823) of Gloucestershire, UK, inoculated (vaccinated) material from the cowpox sores of milkmaid Sarah Nelmes into the arms of several teenage boys. One boy, James Phipps, was subsequently exposed to smallpox and found to be fully protected (1). A less well-known event, termed the "Royal Experiment," preceded Jenner's work by several decades. During the smallpox epidemic of 1721, Caroline, Princess of Wales (daughter of King George I), was understandably concerned that her 3-y-old daughter Mary would become infected. She had heard the rumors from China and Turkey and reports by Cotton Mather of Boston and Lady Mary Worthley Montagu, wife of the British Ambassador to Constantinople, that suggested that cutaneous inoculation of a small amount of material from a smallpox lesion (i.e., variolation) would protect against smallpox. Princess Caroline ordered safety and efficacy tests on six prisoners and five orphan children (including smallpox challenge of the inoculated prisoners). Only then did she allow Dr. Charles Mailtand to inoculate Mary (2). 19th-century immunology. A detailed history of immunology has been published (3), and only a summary is provided here. Rudolf Virchow's 1859 treatise on cellular pathology provided the first formal theory for the cellular basis for disease as opposed to disturbances of the humors (blood, phlegm, black bile, and yellow bile) that had reigned for 2000 y. In th

Type III Mixed Cryoglobulinemia and Antiphospholipid Syndrome in a Patient With Partial DiGeorge Syndrome

We studied a 14 year-old boy with partial DiGeorge syndrome (DGS), status post complete repair of Tetralogy of Fallot, who developed antiphospholipid syndrome (APS) and type III mixed cryoglobulinemia. He presented with recurrent fever and dyspnea upon exertion secondary to right pulmonary embolus on chest computed tomography (CT). Coagulation studies revealed homozygous methylene tetrahydrofolate reductase 677TT mutations, elevated cardiolipin IgM antibodies, and elevated β2-glycoprotein I IgM antibodies. Infectious work-up revealed only positive anti-streptolysin O (ASO) and anti-DNAse B titers. Autoimmune studies showed strongly positive anti-platelet IgM, elevated rheumatoid factor (RF), and positive cryocrit. Renal biopsy for evaluation of proteinuria and hematuria showed diffuse proliferative glomerulonephritis (DPGN) with membranoproliferative features consistent with cryoglobulinemia. Immunofixation showed polyclonal bands. Our patient was treated successfully with antibiotics, prednisone, and mycophenolate mofetil (MMF). This is the first report of a patient with partial DGS presenting with APS and type III mixed cryoglobulinemia possibly due to Streptococcal infection

Hypohidrotic Ectodermal Dysplasia and Immunodeficiency with Coincident NEMO and EDA Mutations

Ectodermal dysplasias (ED) are uncommon genetic disorders resulting in abnormalities in ectodermally derived structures. Many ED-associated genes have been described, of which ectodysplasin-A (EDA) is one of the more common. The NF-κB essential modulator (NEMO encoded by the IKBKG gene) is unique in that mutations result in severe humoral and cellular immunologic defects in addition to ED. We describe three unrelated kindreds with defects in both EDA and IKBKG resulting from X-chromosome crossover. This demonstrates the importance of thorough immunologic consideration of patients with ED even when an EDA etiology is confirmed, and raises the possibility of a specific phenotype arising from coincident mutations in EDA and IKBKG

Immunologic disorders in infants and children

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Intact B-Cell Signaling and Function With Host B-Cells 47 Years After Transplantation for X-SCID.

Introduction: Severe Combined Immunodeficiency (SCID) is a life-threatening immunodeficiency caused by several pathogenic genetic variants, and it is characterized by profound defects in T-cell numbers and immune function. First performed in the late 1960's, hematopoietic stem cell transplantation remains the standard treatment for most cases of SCID. There is a growing number of post-transplant SCID patients, and it is imperative to assess the long-term outcomes of these patients. We have reported here the longest follow-up of a post-transplant SCID patient who, to our knowledge, bears the first gamma chain (γc) variant to show intact IL-21 signaling. Case Presentation: The patient presented at 5 months of age with recurrent thrush and Pneumocystis jiroveci pneumonia. In 1971, at the age of 11 months, he received an unconditioned, matched, related donor transplant comprising whole, unprocessed bone marrow. He is now 48 years old without significant illness and has never required immunoglobulin replacement. He exhibits T-dependent vaccine responses. He does suffer from chronic warts and bacterial infections that have worsened in recent years. We confirmed a known pathogenic variant in the IL2RG gene showing a hemizygous variant NM_000206.2:c.675C>A, resulting in p.Ser225Arg. His chimerism studies revealed donor T cells, host B cells, host myeloid cells, and mixed NK cells. Lymphocyte enumeration revealed normal numbers and distribution of B cells. The host B cells carry the pathogenic variant in IL2RG, but, when stimulated with IL-21, they demonstrated intact, γc-dependent signaling. Conclusions: Even with host B cells, reconstitution with donor T cells can be sufficient to allow over four decades of survival when B-cell function is intact. Our case demonstrates that satisfactory B-cell function can arise as a consequence of both intact IL-21 signaling due to a hypomorphic γc variant, and close HLA matching with the donor to allow for effective T-cell help