2. Update on primary immunodeficiency diseases

doi:10.1016/j.jaci.2005.09.051

Journal of Allergy and Clinical Immunology

Volume 117, Issue 2, Supplement 2, February 2006, Pages S435-S441

https://doi.org/10.1016/j.jaci.2005.09.051 Get rights and content

The pace of discovery in primary immunodeficiency continues to accelerate. In particular, lymphocyte defects have been the source of the most impressive expansion in recent years. Novel forms of agammaglobulinemia, class-switch defects, and T-B⁺ severe combined immunodeficiency have been described. Little by little, the genetic heterogeneity of the common variable immunodeficiency and IgA deficiency phenotypes continues to be unraveled as new molecular defects have been reported in these patients as well. The phenotypic spectrum of DiGeorge syndrome has been further developed, along with promising advances in therapy. Defects of nuclear factor κB regulation and Toll-like receptor signaling have been described, along with defects of chemokine receptors and cytoplasmic proteases. Clinically defined immunodeficiencies, such as hyper-IgE syndrome and idiopathic CD4 lymphocytopenia, are also discussed. Finally, significant adverse effects in some patients have tempered initial enthusiasm for gene therapy.

Section snippets

Antibody deficiencies

A form of agammaglobulinemia with absent B cells in a girl with abnormal facies has been ascribed to alteration of the leucine-rich repeat–containing 8 gene (LRRC8).³ LRRC8 belongs to a family of leucine-rich proteins of unknown function.⁴ In the single patient described, a balanced chromosomal translocation permitted expression of a truncated molecule that exhibited dominant negative activity. B-cell development was arrested in the bone marrow, as in other forms of agammaglobulinemia.⁵

Cellular deficiencies

Idiopathic CD4 lymphocytopenia is a rare immunodeficiency of unknown cause that clinically closely resembles HIV infection, but the absence of this and related viruses by means of all serologic and molecular methods of detection is a crucial element of the case definition.²⁰ Patients have persistently low CD4 T-cell counts (<300 cells/mm³) and experience opportunistic infections, autoimmune disease, and hematologic malignancies.

As yet poorly characterized isolated defects of natural killer (NK)

Combined deficiencies

A novel form of T⁻B⁺NK⁺ SCID has been described in association with defects of the CD3δ chain (CD3D mutation).²⁴ The CD3 complex transduces signals initiated by interaction of the T-cell receptor with an MHC-peptide complex. Defects of other components of the CD3 complex (γ and ɛ chains) and associated kinases (ζ-associated protein, 70 kd) have been associated with SCID or deficient cellular immunity.1, 2 Interestingly, SCID caused by a CD3δ defect might be distinct from others in that a thymus

Phagocyte defects

It is now clear that both cyclic neutropenia and a subset of Kostmann's syndrome, or congenital agranulocytosis, can result from deficiency of elastase 2.⁴⁵ Mutations in the granulocyte colony-stimulating factor receptor (CSF3R gene) that had previously been identified in patients with Kostmann's syndrome were found to have been acquired, possibly because of an underlying genetic instability in this disorder. Note that X-linked neutropenia has been associated with particular mutations of the

Therapy of immunodeficiency

Two forms of SCID have been treated successfully with gene therapy: X-linked SCID (IL2RG mutation) and adenosine deaminase deficiency.49, 50 Approximately 20 patients in France, the United Kingdom, and the United States have been treated this way. Unfortunately, leukemia has developed in 3 patients thus far, apparently because of integration of the vector in a sensitive site for regulation of cell division (the LMO2 gene).⁵¹ For this reason, gene therapy trials are currently under review.

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Bacillus Calmette-Guérin vaccination is routinely administered to infants in Iran within the first month of life, usually at birth. BCGitis is a complication we might see in non-PID patients but along with other infections one should doubt if there is an underlying cause.33 The third patient with SCID was a four-month-old girl diagnosed with cytomegalovirus (CMV) pneumonia.
The prevalence of undiagnosed primary immunodeficiency diseases is remarkably high and contributes to increasing the rate of morbidity and mortality among this group of patients.
To examine the 10 warning sign scoring system in patients suspected of primary immune deficiency and also estimate the diagnostic delay in patients with proven disease.
This descriptive cross-sectional study was carried out during the years 2015–2016 in Ali Asghar (AS) Clinic and Hospital. Two hundred patients with suspected primary immune deficiency disease were eligible for inclusion in the study. Multivariable logistic regression analysis was used to determine the relation between findings.
In this study, the majority of suspected cases of immunodeficiency were males (57%) with a mean age of 3.33 ± 2.89 years. Twenty-one (10.5%) patients were diagnosed with immunodeficiency disease. The mean diagnostic delay among primary immune deficient patients was 2.05 ± 1.7 years. There was a significant relationship between having parental consanguinity (OR = 2.68, 95% CI: 1.07–6.70), allergies (OR = 5.03, 95% CI: 1.13–22.31), vaccine adverse effects (OR = 9.31, 95% CI: 1.24–69.96) and primary immune deficiency diagnosis. No association was observed between age (OR = 0.98, 95% CI: 0.84–1.14), gender (OR = 0.99, 95% CI: 0.39–2.47), immune deficiency scoring (OR = 0.68, 95% CI: 0.31–1.45) and primary immune deficiency diagnosis.
Ten warning sign scoring system is of less value to consider a patient suspected of having primary immune deficiency. There is a meaningful delay in diagnosis of primary immune deficiencies especially in antibody deficiency defects which seeks further upgrading of knowledge in physicians.
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La fiebre recurrente es un problema relativamente frecuente en la infancia. En la mayoría de las ocasiones es sencillo establecer su etiología generalmente asociada a episodios infecciosos banales. No obstante, en un pequeño porcentaje de casos estos episodios se deben a procesos de causa no infecciosa a menudo de complejo diagnóstico. En este documento se analiza el diagnóstico diferencial de la fiebre recurrente o periódica frente a otros procesos, con especial atención a las enfermedades autoinflamatorias (EA). Las EA son alteraciones de la inmunidad innata recientemente incluidas dentro de las inmunodeficiencias, sin embargo no se caracterizan por presentar infecciones lo que las diferencia de las inmunodeficiencias clásicas. Un importante número de las EA tienen una base genética conocida. La sintomatología que ocasionan se deriva de una inflamación sistémica que puede dar clínica y procesos muy variados. Uno de los grupos mejor conocidos es el formado por los síndromes hereditarios de fiebre periódica. Este grupo se caracteriza por presentar fiebre recurrente, asociada a diversos síntomas, con una relativa periodicidad y con intervalos libres o casi libres de síntomas. Para algunas de las entidades más frecuentes se dispone de criterios diagnósticos que son aquí recogidos, así como las características que deben hacernos iniciar el estudio genético. El tratamiento debe ser individualizado dada la complejidad de estos cuadros si bien se pueden dar algunas recomendaciones generales.
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2. Update on primary immunodeficiency diseases

Section snippets

Antibody deficiencies

Cellular deficiencies

Combined deficiencies

Phagocyte defects

Therapy of immunodeficiency

J Allergy Clin Immunol

Ann Allergy Asthma Immunol

FEBS Lett

Trends Genet

Clin Immunol

Blood

Clin Immunol

Blood

Clin Immunol

Clin Immunol

Microbes Infect

Blood

Blood

Lancet

Blood

J Allergy Clin Immunol

Clin Immunol

Blood

Blood

J Allergy Clin Immunol

J Allergy Clin Immunol

Cell Biol Int

Semin Hematol

J Pediatr

Lancet