scholarly journals Treatment of immune-mediated cytopenias in patients with primary immunodeficiencies and immune regulatory disorders (PIRDs)

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 673-679
Author(s):  
Markus G. Seidel
Keyword(s):  
Lupus Erythematosus ◽  
Bone Marrow Failure ◽  
Primary Immunodeficiencies ◽  
Definitive Treatment ◽  
Inborn Errors ◽  
Hematopoietic Stem ◽  
Rheumatologic Diseases ◽  
Inborn Errors Of Immunity ◽  
Immune Mediated ◽  
Regulatory Disorders

Abstract Severe immune cytopenias (SICs) are rare acquired conditions characterized by immune-mediated blood cell destruction. They may necessitate emergency medical management and long-term immunosuppressive therapy, strongly compromising the quality of life. The initial diagnostic workup involves excluding malignancies, congenital cytopenias, bone marrow failure syndromes, infections, and rheumatologic diseases such as systemic lupus erythematosus. Causal factors for SIC such as primary immunodeficiencies or immune regulatory disorders, which are referred to as inborn errors of immunity (IEIs), should be diagnosed as early as possible to allow the initiation of a targeted therapy and avoid multiple lines of ineffective treatment. Ideally, this therapy is directed against an overexpressed or overactive gene product or substitutes a defective protein, restoring the impaired pathway; it can also act indirectly, enhancing a countermechanism against the disease-causing defect. Ultimately, the diagnosis of an underling IEI in patients with refractory SIC may lead to evaluation for hematopoietic stem cell transplantation or gene therapy as a definitive treatment. Interdisciplinary care is highly recommended in this complex patient cohort. This case-based educational review supports decision making for patients with immune-mediated cytopenias and suspected inborn errors of immunity.

Rheumatological Diseases in Patients with Inborn Errors of Immunity in the USIDNET Registry

2021 ◽  
Author(s):  
Nurcicek Padem ◽  
Hannah Wright ◽  
Ramsay Fuleihan ◽  
Elizabeth Garabedian ◽  
Daniel Suez ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Chronic Mucocutaneous Candidiasis ◽  
Inborn Errors ◽  
Rheumatologic Diseases ◽  
Disease Patterns ◽  
Inborn Errors Of Immunity ◽  
Number Of Patients ◽  
Rheumatological Disease ◽  
Male Patients ◽  
Rheumatological Diseases

Abstract Purpose There is a gap in clinical knowledge regarding associations between specific inborn errors of immunity (IEIs) and rheumatological diseases. In this study, we report the frequency of rheumatological conditions in a large cohort of patients with IEI using the USIDNET (United States Immunodeficiency Network) registry. Methods We used the USIDNET registry to conduct the analysis. We included all IEI patients within the registry for whom a diagnosed rheumatological disease was reported. Results The total number of patients with IEI in our query was 5058. Among those, 278 (5.49%) patients had a diagnosis of rheumatological disease. This cohort included 172 (61.8%) female and 106 (38.2%) male patients. Rheumatologic complications were highest in the interferonopathies (66.6%), autoimmune lymphoproliferative syndrome (ALPS) (13.7%) and Immunoglobulin G subclass deficiency (IgGSD) (11.11%). Additionally, disease patterns were noted to be different in various IEI disease groups. Inflammatory myopathies were the most common rheumatologic condition in patients with X-linked agammaglobulinemia (1.65%), Sjogren’s syndrome was the most common rheumatology disease reported in ALPS patients (6.85%) and systemic lupus erythematosus was the most common rheumatology disease in in patients with Chronic mucocutaneous candidiasis(CMC) (7.41%). Rheumatoid arthritis (RA) report rate was highest in patients with IgGSD (3.70%), specific antibody deficiency (3.66%), and ALPS (2.74%). Conclusion This study reports that rheumatologic diseases are frequently observed in patients with IEI. The frequency of different rheumatological disease was variable based on the underlying diagnosis. Clinicians caring for patients with IEI should be vigilant to monitor for rheumatologic complications.

Immunogenetic Analysis Reveals the Association of INF-γ (+874 A/T) Hypersecretor Genotype in AA and a Low Frequency of KIR-2DL3/C1 Mismatch in Responders to Immunosuppression.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1700-1700
Author(s):  
Bianca Serio ◽  
Giridharan Ramsingh ◽  
Ramon Tiu ◽  
Antonio M. Risitano ◽  
Mikkael A. Sekeres ◽  
...  
Keyword(s):  
Cytotoxic T Cells ◽  
Bone Marrow Failure ◽  
Receptor Gene ◽  
Low Frequency ◽  
Hematopoietic Stem ◽  
Hla Ligand ◽  
Bone Marrow Failure Syndromes ◽  
Immune Mediated ◽  
Self Tolerance ◽  
Tnf Α

Abstract Clinical and laboratory evidence support an immune pathogenesis in most cases of idiopathic aplastic anemia (AA) and closely related disorders such as paroxysmal nocturnal hemoglobinuria (PNH). While external triggers are likely necessary, a complex constellation of immunogenetic factors may determine disease susceptibility. Many immunogenetic factors can influence the quality of immune response and affect the propensity to immune-mediated attack on hematopoietic stem cells in AA. Here we investigated whether KIR and KIR-L (HLA-A) genotype and cytokine/receptor gene variants are over-represented in AA and PNH. We studied a cohort of 77 patients with AA (23 AA, 20 AA/PNH and 34 PNH), 10 with hypocellular MDS and 175 healthy controls. The following SNPs in immunoregulatory genes were analyzed: IL-1α (−889 T/C), IL-2 (−330 T/G +166 G/T), IL-4 (−1098 T/G −590 T/C −33 T/C), IL-1R (−1970 C/T), IL-1Rα (mspa111100 T/C), IL-4RA (+ 190 G/A), IL-1β (−511 C/T, +3962 T/C), IL-6 (−174 C/G, nt565 G/A), IL-10 (−1082 G/A, −819 C/T, −592 C/A), IL-12 (−1188 C/A), TGF-β (+10 C/T, +25 G/C), INF-γ (+874 A/T), TNF-α (−308 G/A, −238 G/A) and immunomodulatory receptor genes including CTLA-4 exon 6 (+49 G/A), FcRIIIa (158 F/V) and CD45-exons 6 (+138 A/G), and 4 (+54 A/G, +77 C/G). As binding of KIR to the appropriate HLA ligand (KIR-L) can modulate activation of NK and cytotoxic T cells, we examined the combined impact of KIR/KIR-L genotypes on the risk of AA and PNH syndrome. In AA we found a decreased frequency of inhibitory KIR-2DL3 genes (68% vs. 89%, p=.0002); analysis of the KIR genotype in correlation with the corresponding KIR-L profile, revealed a decreased frequency of stimulatory 2DS1/C2 mismatch resulting in a potentially enhanced cytotoxic activity (14% vs.44%, p=.003). No association was found for most of the SNPs tested. However, when we examined the frequency TGF-β genotypes, increased frequency of GG variant in codon 25 (61% vs. 35% in controls, p=.03), associated with the “high secretor” phenotype, was found in AA. This relationship was also present in hypocellular MDS (82% vs. 32%, p=.007). Additionally, we found a lower incidence of TT genotypes for the IL-1Rα gene (33% vs. 62% p=.02). We confirm that the hypersecretor genotype T/T of INF-γ was over-represented in AA (28% vs. 10% in controls, p=.02). Subgroup analysis revealed that the T/T genotype of IFN-γ (35% vs. 14% p=.01) correlated with presence of a PNH clone. Previously, we have shown the association of HLA-DR15 with responsiveness to immunosuppression. When AA patients were subgrouped according to response to ATG/CsA, therapy refractoriness correlated with the presence of the C2/C2 haplotype (30% vs. 0% p=.02) and inhibitory KIR-2DL3/C1 mismatch (70% vs. 0%, p=.01) which may result in a greater propensity to breach of self-tolerance. In comparison, in the total AA group, C2/C2 haplotype and KIR-2DL3/C1 mismatch were present in 17% vs. 24% and 8% vs. 16% of controls, respectively. An increase in the frequency of 2DL3 and a decrease in 2DS1 mismatch may result in imbalance between cytotoxicity and KIR inhibition. In sum, our findings demonstrate that complex inherited traits involving immunogenetic factors may genetically determine propensity to bone marrow failure syndromes.

scholarly journals Infectious Agents and Bone Marrow Failure: A Causal or a Casual Connection?

2021 ◽  
Vol 8 ◽  
Author(s):  
Valentina Giudice ◽  
Antonio M. Risitano ◽  
Carmine Selleri
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Indirect Evidence ◽  
Cell Receptor ◽  
Cross Reactivity ◽  
Autoimmune Response ◽  
Hematopoietic Stem ◽  
Immune Mediated ◽  
Viral Particles ◽  
Cellular Components

Acquired bone marrow failure (BMF) syndromes are considered immune-mediated disorders because hematological recovery after immunosuppressive therapies is the strongest indirect evidence of the involvement of immune cells in marrow failure development. Among pathophysiology hypotheses, immune derangement after chronic antigen exposure or cross-reactivity between viral particles and cellular components are the most accepted; however, epitopes against whom these lymphocytes are directed to remain unknown. In this study, we showed that BMF-associated immunodominant clones, namely the most represented T cells carrying an antigen-specific T-cell receptor (TCR) sequence in a random pool, were frequently associated with those described in various infectious diseases, such as cytomegalovirus (CMV) and Mycobacterium tuberculosis infection. We hypothesize that these pathogens might elicit an autoimmune response triggered by cross-reactivity between pathogen-related components and proteins or might be expanded as an unspecific response to a global immune dysregulation during BMF. However, those frequent intracellular pathogens might not only be passengers in marrow failure development, while playing a central role in starting the autoimmune response against hematopoietic stem cells.

scholarly journals Genetic Associations in Acquired Immune-Mediated Bone Marrow Failure Syndromes: Insights in Aplastic Anemia and Chronic Idiopathic Neutropenia

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Irene Mavroudi ◽  
Helen A. Papadaki
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Transforming Growth Factor ◽  
Bone Marrow Failure ◽  
Genetic Associations ◽  
Hematopoietic Stem ◽  
Bone Marrow Failure Syndromes ◽  
Immune Mediated ◽  
Chronic Idiopathic Neutropenia ◽  
Activated T Lymphocytes

Increasing interest on the field of autoimmune diseases has unveiled a plethora of genetic factors that predispose to these diseases. However, in immune-mediated bone marrow failure syndromes, such as acquired aplastic anemia and chronic idiopathic neutropenia, in which the pathophysiology results from a myelosuppressive bone marrow microenvironment mainly due to the presence of activated T lymphocytes, leading to the accelerated apoptotic death of the hematopoietic stem and progenitor cells, such genetic associations have been very limited. Various alleles and haplotypes of human leucocyte antigen (HLA) molecules have been implicated in the predisposition of developing the above diseases, as well as polymorphisms of inhibitory cytokines such as interferon-γ, tumor necrosis factor-α, and transforming growth factor-β1 along with polymorphisms on molecules of the immune system including the T-bet transcription factor and signal transducers and activators of transcription. In some cases, specific polymorphisms have been implicated in the outcome of treatment on those patients.

scholarly journals The Use of Biologic Modifiers as a Bridge to Hematopoietic Cell Transplantation in Primary Immune Regulatory Disorders

2021 ◽  
Vol 12 ◽  
Author(s):  
Danielle E. Arnold ◽  
Deepak Chellapandian ◽  
Jennifer W. Leiding
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Clinical Manifestations ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Inborn Errors ◽  
Immune Mediated ◽  
Definitive Therapy ◽  
Regulatory Disorders

Recently, primary immune regulatory disorders have been described as a subset of inborn errors of immunity that are dominated by immune mediated pathology. As the pathophysiology of disease is elucidated, use of biologic modifiers have been increasingly used successfully to treat disease mediated clinical manifestations. Hematopoietic cell transplant (HCT) has also provided definitive therapy in several PIRDs. Although biologic modifiers have been largely successful at treating disease related manifestations, data are lacking regarding long term efficacy, safety, and their use as a bridge to HCT. This review highlights biologic modifiers in the treatment of several PIRDs and there use as a therapeutic bridge to HCT.

scholarly journals AWARENESS OF DOCTORS AND PATIENTS ABOUT INBORN ERRORS OF IMMUNITY

2020 ◽  
Vol 11 (4) ◽  
pp. 16-21
Author(s):  
E.V. Zaitseva ◽  
Keyword(s):  
Quantitative Research ◽  
Complex Disease ◽  
Clinical Manifestations ◽  
The Body ◽  
Primary Immunodeficiencies ◽  
Malignant Neoplasms ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Child Patient ◽  
Primary Care Doctors

The immune system protects the body. When defenses are compromised, people with hereditary immunological disorders become vulnerable to many life-threatening infections. Inborn errors of immunity (primary immunodeficiencies), manifested in patients in increased susceptibility to infectious diseases, autoimmune diseases, allergies, and malignant neoplasms. Today, this group of diseases is still considered quite rare. However, the development of diagnostic technologies expands the list of nosologies associated with inborn errors of immunity. Neonatal screening for inborn errors of immunity could solve many of the problems of these patients, but the procedure is not carried out in the Russian Federation. Therefore, diagnostics based on an analysis of the clinical manifestations of diseases. In most cases, the disease is diagnosed in early childhood. Here, the role of both the parents of the child-patient and the medical staff is important. The health and life of the child depends on their awareness of the disease, methods of diagnosis, treatment. This group of diseases is chronic, under an hour, severe. In the absence of timely diagnosis and proper therapy, it can be fatal. The article describes the experience of applied quantitative research conducted by the method of questioning patients with primary immunodeficiencies (parents of underage patients), about their disease, methods of treatment, problems arising in the long-term struggle with this complex disease. The author notes that patients and primary care doctors or general practitioners are poorly informed about diseases associated with primary immunodeficiencies. It is concluded that it is necessary to increase the informational medical culture of the population, especially the young, as participants in the interaction "doctor-patient" and representatives of the interests of minor children-patients with inborn errors of immunity.

How I Treat: Allogeneic HSCT for adults with Inborn Errors of Immunity

Blood ◽  
2021 ◽  
Author(s):  
Siobhan Burns ◽  
Emma C Morris
Keyword(s):  
Patient Selection ◽  
Severe Disease ◽  
Severe Infection ◽  
Cell Transplant ◽  
Inherited Disorders ◽  
Inborn Errors ◽  
Hematopoietic Stem ◽  
Inborn Errors Of Immunity ◽  
Long Term Follow Up ◽  
History Of

Inborn Errors of Immunity (IEI) are rare inherited disorders arising from monogenic germline mutations in genes that regulate the immune system. The majority of IEI are Primary Immunodeficiencies characterised by severe infection often associated with autoimmunity, autoinflammation and/or malignancy. Allogeneic hematopoietic stem cell transplant (HSCT) has been the corrective treatment of choice for many IEI presenting with severe disease in early childhood and experience has made this a successful and comparatively safe treatment in affected children. Early HSCT outcomes in adults were poor, resulting in extremely limited use worldwide. This is changing due to a combination of improved IEI diagnosis to inform patient selection, better understanding of the natural history of specific IEI and improvements in transplant practice. Recently published HSCT outcomes for adults with IEI have been comparable with pediatric data, making HSCT an important option for correction of clinically severe IEI in adulthood. Here we discuss our practice for patient selection, timing of HSCT, donor selection and conditioning, peri- and post HSCT management and our approach to long term follow up. We stress the importance of multidisciplinary involvement in the complex decision-making process that we believe is required for successful outcomes in this rapidly emerging area.

scholarly journals Stem Cell-Based Disease Models for Inborn Errors of Immunity

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 108
Author(s):  
Aline Zbinden ◽  
Kirsten Canté-Barrett ◽  
Karin Pike-Overzet ◽  
Frank J. T. Staal
Keyword(s):  
Stem Cell ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Disease Models ◽  
Inborn Errors ◽  
Hematopoietic Stem ◽  
Inborn Errors Of Immunity ◽  
Induced Pluripotent

The intrinsic capacity of human hematopoietic stem cells (hHSCs) to reconstitute myeloid and lymphoid lineages combined with their self-renewal capacity hold enormous promises for gene therapy as a viable treatment option for a number of immune-mediated diseases, most prominently for inborn errors of immunity (IEI). The current development of such therapies relies on disease models, both in vitro and in vivo, which allow the study of human pathophysiology in great detail. Here, we discuss the current challenges with regards to developmental origin, heterogeneity and the subsequent implications for disease modeling. We review models based on induced pluripotent stem cell technology and those relaying on use of adult hHSCs. We critically review the advantages and limitations of current models for IEI both in vitro and in vivo. We conclude that existing and future stem cell-based models are necessary tools for developing next generation therapies for IEI.

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