Hematopoietic Stem Cell Transplantation for Multiple Sclerosis
Richard K. Burt, Alberto M. Marmont in Stem Cell Therapy for Autoimmune Disease, 2019
HSCT has an infection-associated mortality risk that is related to the intensity of the conditioning regimen. Three or more intense conditioning agents such as busulfan, cyclophosphamide, and ATG or cyclophosphamide, TBI, and ATG, or BEAM and ATG when combined with CD34+ selection may cause opportunistic infectious deaths. For example, with a conditioning regimen of total body irradiation (TBI) (800 cGy), cyclophosphamide (120 mg/kg), rabbit ATG (15 mg/kg) and CD34+ positive selection, a patient died from Epstein-Barr virus (EBV) associated post-transplant lymphoproliferative disorder (PTLD).22 A late death from pneumoccocus bacteremia has been reported after busulfan (16 mg/kg), cyclophosphamide (120 mg/kg), and anti-thymocyte globulin (30 mg/kg) combined with CD34+ selection.23 This may have been secondary to prolonged immune deficiency-related hypogammaglobulinemia. Aspergillous, which is also an opportunistic infection related to immune suppression, occurred following the combination of BEAM/ATG and CD34+ selection.9 Therefore, less intense regimens that omit at least one of these agents, such as CD34+ selection or ATG or TBI and/or continues the same drugs at lower doses, should be considered for phase II/III trials.
Unexplained Fever In Hematologic Disorders
Benedict Isaac, Serge Kernbaum, Michael Burke in Unexplained Fever, 2019
B-CLL lymphocytes are immunologically dysfunctional. Severe hypogammaglobulinemia may be present in patients who have asymptomatic disease and will eventually develop in some 50% of the patients. Inversion of T-helper/T-suppressor ratio, a decreased T-helper function and increased numbers of T-suppressor cells have been described in B-CLL.70 The absent or inadequate antibody response underlies the marked susceptibility of CLL patients to infections, commonly with encapsulated microorganisms.70-71 In patients with severe hypogammaglobulinemia and recurrent infections, administration of gammaglobulin, in particular intravenous immunoglobulin, may be of benefit.72 Paradoxically, autoantibodies, autoimmune hemolytic anemia and immune thrombocytopenia occur with increased frequency.
Mucosal manifestations of immunodeficiencies
Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald in Principles of Mucosal Immunology, 2020
The nuclear factor kappa B (NF-κB) is a multimeric transcription factor that regulates a variety of cellular processes, including innate and adaptive immune responses. Activation of NF-κB is regulated by a complex consisting of two catalytic protein subunits with kinase activity (IKKα and IKKβ) and a regulatory component, IKKγ (also known as NF-κB essential modulator, or NEMO), which function to phosphorylate and deactivate IκB, an inhibitor of NF-κB. NEMO is encoded by a gene (IKBKG) located on the X chromosome. In humans, null IKBKG gene mutations lead to incontinentia pigmenti in heterozygous females, and result in embryonic lethality in males. In contrast, hypomorphic mutations in males result in X-linked immunodeficiency with ectodermal dystrophy. Typical manifestations of the disease include scanty hair, defective tooth formation with conical teeth, nail defects, hypohidrosis, increased susceptibility to recurrent infections (including mycobacterial disease), and aberrant inflammatory responses. Most patients show hypogammaglobulinemia, with reduced IgG levels and defective antibody responses. Impaired T-cell priming and defective cytolytic function of NK cells are also present. There is significant variability in the severity of the clinical phenotype. Treatment is based on immunoglobulin replacement therapy and prompt treatment of infections.
How do nuclear factor kappa B (NF-κB)1 and NF-κB2 defects lead to the incidence of clinical and immunological manifestations of inborn errors of immunity?
Published in Expert Review of Clinical Immunology, 2023
Nazanin Fathi, Hanieh Mojtahedi, Marzieh Nasiri, Hassan Abolhassani, Mahsa Yousefpour Marzbali, Marzie Esmaeili, Fereshte Salami, Furozan Biglari, Nima Rezaei
NF-κB1 and NF-κB2 deficiencies generally belong to primary antibody deficiencies according to the International Union of Immunological Societies (IUIS) classification [1]. Hypogammaglobulinemia is the most often immunologically distinguished manifestation in these patients. Low antibody production may result from a defect in terminal B cell development. Two lineages of B cells can progress to antibody secretion basis on their anatomic localization and ontogeny: the B1 lineage and B2 lineage, which consist of FO B cells and MZ B cells. As previously mentioned, B1 and MZ B cells are the main sources of natural antibodies and mediate rapid responses by producing IgM antibodies almost 1–3 days after exposure to antigens. This compensates for the temporal gap to produce FO B cell-derived IgG antibodies caused by a delay (about 7 days). Generally, the significant characteristics of humoral immunity are producing high-affinity, isotype-switched antibodies generated by plasma cells, and long-lived memory B cells. Both mechanisms are defective in patients with NF-κB mutations.
The First Iranian Cohort of Pediatric Patients with Activated Phosphoinositide 3-Kinase-δ (PI3Kδ) Syndrome (APDS)
Published in Immunological Investigations, 2022
Saba Fekrvand, Samaneh Delavari, Zahra Chavoshzadeh, Roya Sherkat, Seyed Alireza Mahdaviani, Mahnaz Sadeghi Shabestari, Gholamreza Azizi, Mohammad Taghi Arzanian, Bibi Shahin Shamsian, Shabnam Eskandarzadeh, Narges Eslami, William Rae, Antonio Condino-Neto, Javad Mohammadi, Hassan Abolhassani, Reza Yazdani, Asghar Aghamohammadi
1. Hyper IgM (HIgM) characterized by normal or increased serum level of IgM along with decreased serum level of IgA and IgG; 2. Hypogammaglobulinemia characterized by decreased serum levels of at least one of IgG, IgA or IgM serum levels; 3. Agammaglobulinemia characterized by serum IgG level below 200 mg/dl in infants aged <12 months and 500 mg/dl in children aged >12 months or normal IgG levels with IgA and IgM below 2 standard deviations (SD) and 4. IgA deficiency (IgAD) characterized by serum levels of IgG and IgM within the age- and sex-matched reference values but IgA below 2SD. Hypogammaglobulinemia, agammaglobulinemia and IgAD profiles were equally frequent among APDS1 group (all in two patients, 33.3%), while HIgM (five patients, 55.6%) followed by hypogammaglobulinemia (three patients, 33.3%) and IgAD (one patient, 11.1%) were the more common profiles among APDS2 patients. Median absolute counts of all lymphocyte subsets as well as the median of all Ig levels including IgG and IgA (except IgM) were lower in patients with APDS2 than APDS1 group, although these differences were not significant.
Imatinib-Induced Hypogammaglobulinemia in Children and Adolescents with Chronic Myeloid Leukemia
Published in Pediatric Hematology and Oncology, 2020
Sidharth Totadri, Shankar Thipparapu, Ritu Aggarwal, Madhulika Sharma, Shano Naseem, Richa Jain, Amita Trehan, Pankaj Malhotra, Neelam Varma, Deepak Bansal
Seventeen percent of patients had pan-hypogammaglobulinemia in our cohort of 30 children and adolescents with CML receiving imatinib for a median duration of 6 years. The limitations of the study include the cross-sectional design, which precluded follow up of serum immunoglobulin levels over time. Besides, a lymphocyte subset analysis was not performed. There was no normative data available for normal serum immunoglobulin levels in Indian children (> 5 years) at the time of performing the study. Hence, international reference ranges were utilized.10 Nevertheless, pediatric CML is a rare disorder, and this is one of the first studies dedicated to evaluating serum immunoglobulin levels in children and adolescents. One seldom encounters recurrent, severe, or unusual infections in children with CML-CP receiving TKI therapy in clinical practice. However, we have not collected data on the occurrence of infection in our study. The paucity of infections requiring clinical attention in children with CML is a factor that limits the evaluation of the clinical impact of hypogammaglobulinemia. The clinical repercussion of the hypogammaglobulinemia is uncertain. There are reports that treatment with TKI therapy may be associated with an increased risk of infections, including reemergence of viral infections.15–17