Disorders of lymphobioesis.ppt

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Information about Disorders of lymphobioesis.ppt

Published on September 26, 2018

Author: AbdulKaderSouid

Source: slideshare.net

1. Abdul-Kader Souid Primary Immune Deficiency (PID) → ↑Infections + ↑Autoimmunity + ↑Inflammation (macrophage activation syndrome) + ↑Malignancy Disorders of Lymphopoiesis (1) B Cell Deficiency = ↓CD19+ + ↓IgA, IgG, IgM + Bacterial infections • Agammaglobulinemia, X-linked; XLA; XLR (MIM#300755); BTK (Bruton agammaglobulinemia tyrosine kinase; MIM#300300). (2) T Cell Deficiency = ↓CD3+ (lymphopenia) + Bacterial/ viral/ fungal infections • DiGeorge syndrome; DGS; AD (MIM#188400); TBX1 (T-BOX 1; MIM#602054); 1.5-3.0 Mb hemizygous deletion of 22q11.2 (haploinsufficiency of TBX1) or point mutations in TBX1. Immunodeficiency → Live vaccines (BCG, varicella, MMR) are contraindicated (3) Severe combined immunodeficiency (SCID), autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (MIM#102700); AR; ADA (adenosine deaminase; MIM#608958). Must know https://www.immunodeficiencysearch.com

2. Lymphopoiesis • Lymphopoiesis = Hematopoietic multipotent cells → B cells, T cells, natural killer (NK) cells, and dendritic cells • B Cells (CD19+) = Expression of surface B cell receptor (BCR) (surface immunoglobulin + CD79a + CD79b). • T Cells (CD3+) = Expression of surface T cell receptors (TCR) associated with CD3 proteins. CD = Cluster of DifferentiationMust know T cell

3. Primary Immune Deficiency → ↑Infections + ↑Autoimmunity + ↑Inflammation (MAS) + ↑Malignancies • Recurrent respiratory infections (otitis, sinusitis, bronchiectasis, pneumonia) • Invasive infections (bones, joints, liver) • Purulent lymphadenitis • Skin/ deep tissue abscesses • Infections by poorly virulent / opportunistic pathogens (Pneumocystis jiroveci, cytomegalovirus, mycobacteria, Cryptosporidium, Giardia lamblia) • Persistent/ recurrent candidiasis (T cell deficiency) • Failure to thrive Primary Immune Deficiency (PID) Dilated bronchi (bronchiectasis) in a 13-year-old boy with agammaglobulinemia Pneumocystis jiroveci pneumonia Must know https://www.immunodeficiencysearch.com

4. The 12 Warning Infant Signs of PID 1. Familial history of PID or early death due to infection 2. Severe/ persistent fungal, viral, or bacterial infections 3. Persistent lymphopenia (<1.5 x109/L) 4. Absence of thymic shadow on CXR 5. Adverse reaction to live vaccine (MMR, BCG and varicella) Pediatric Allergy and Immunology 2011;22:345–346 6. Congenital heart defects/ cleft palate/ face anomaly/ developmental delay (22q11.2 deletion) 7. Hypocalcemia (22q11.2 deletion) 8. Autoimmune disorder 9. Sepsis-like clinical picture without microbial isolation 10. Extensive skin lesions 11. Persistent diarrhea 12. Delayed umbilical cord detachment (>30 days) Must know

5. Panel A: Patient skin lesions showing erythematous nodules. Panels A-C. H&E stain of a skin excisional lesion showing infiltration by histiocytes in the dermis. Panels D-E :H&E stain of bone marrow biopsy showing infiltration by histiocytes. Panel F .Bone marrow specimen revealing infiltration by histiocytes ingesting acid-fast bacilli. A B C D E F A female infant received BCG at birth. She presents at four months of age with fever and erythematous skin nodules. Family history is significant for familial histiocytic lymphohistocytosis (HLH) involving her brother. Histology of skin and marrow revealed infiltration by histiocytes ingesting acid-fast bacilli. How can we avoid administering BCG to neonates with immunodeficiency? Al-Hammadi S, Alsuwaidi AR. Disseminated Bacillus Calmette-Guérin (BCG) infections in infants with immunodeficiency. BMC Res Notes. 2017 May 5;10(1):177. Optional

6. For Adults The 10 warning signs of the Jeffrey Modell Foundation (http://www.info4pi.org) Optional

7. For Children The 10 warning signs of the Jeffrey Modell Foundation (http://www.info4pi.org) Optional

8. http://www.info4pi.org/library/educational-materials/10-warning-signs Must know Al-Mekaini LA, … Alsuwaidi AR. Seroprevalence of vaccine-preventable diseases among young children in the United Arab Emirates. Int J Infect Dis. 2016 Sep;50:67-71.

9. A 5-month-old male infant with fever His lymphocyte count is 1.1 x109/L (= 1,100/mL). Lymphocyte surface markers (immunophenotyping) shows: CD3+ T cells = 800/µL (10th percentile = 2,500/µL) • CD4+ T cells = 50/µL (10th percentile = 1,600/µL) • CD8+ T cells = 750/µL (10th percentile = 560/µL) CD19+ B cells = 60/µL (10th percentile = 300/µL) NK cells = 102/µL (normal) T cells constitute ~70% of circulating lymphocytes. Thus, T cell immune deficiency is associated with lymphopenia. Newborn screening for T cell immunodeficiency is based on absence of small circles (TREC, T cell receptor excision circles) of DNA created in T cells during V(D)J recombination. RSS, recombination signal sequences TREC Must know

10. BTK encodes a cytoplasmic protein involved in B cell maturation. BTK binding to phosphatidylinositol (3,4,5)- trisphosphate (PIP3) → ↑activity of downstream proteins involved in B cell signaling. Ibrutinib is a selective inhibitor of Bruton tyrosine kinase (Btk). It is approved for treatment of B-cell malignancies. Ibrutinib B Cell Deficiency = ↓CD19+ + ↓IgA, IgG, IgM + Bacterial infections • Agammaglobulinemia, X-linked; XLA; XLR (OMIM#300755); BTK (Bruton agammaglobulinemia tyrosine kinase; OMIM#300300). Cytoplasm Extracellular Must know

11. T Cell Deficiency = ↓CD3+ (lymphopenia) + Bacterial/ viral/ fungal infections • DiGeorge syndrome; DGS; AD (OMIM#188400); TBX1 (T-BOX 1; OMIM#602054); 1.5-3.0 Mb hemizygous deletion of 22q11.2 (haploinsufficiency of TBX1) or point mutations in TBX1. DGS presents with a variety of phenotypes, that include Cardiac defect (e.g., tetralogy of Fallot), Abnormal face, T cell (thymic) hypoplasia, Cleft palate, and Hypocalcemia (neonatal hypoparathyroidism) as a result of 22q11 deletion (CATCH22). The T-box genes are transcription factors involved in the regulation of developmental processes. Must know

12. In ADA deficiency, T and B cells accumulate the apoptosis-inducing toxins adenosine, deoxyadenosine, and deoxyadenosine triphosphate (dATP). ribonucleotide reductase Severe combined immunodeficiency (SCID), autosomal recessive, T cell- negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (MIM#102700); AR; ADA (adenosine deaminase; MIM#608958). The diagnosis is made by ↓enzyme activity in erythrocytes or ADA gene sequencing. Must know

13. Must Know Pearls • Primary immune deficiency (PID) increases susceptibility to infection, autoimmunity (AHA, ITP, T1D, thyroiditis), inflammation (macrophage activation syndrome), and malignancy. • Live vaccines (BCG, varicella, MMR) are contraindicated in PID. • Work-up includes CBC, chest radiograph, immunoglobulin levels, specific antibody response (tetanus, diphtheria), and lymphocyte surface marker. • T cell immunodeficiency is associated with lymphopenia. • TREC is a screening marker for T cell immunodeficiency. 9/26/2018 13

14. Required Reading 1. Wood P, Stanworth S, Burton J, et al. Recognition, clinical diagnosis and management of patients with primary antibody deficiencies: a systematic review. Clin Exp Immunol 2007;149:410. 2. Ballow M. Approach to the patient with recurrent infections. Clin Rev Allergy Immunol 2008;34:129. 3. Carneiro-Sampaio M, Jacob CM, Leone CR. A proposal of warning signs for primary immunodeficiencies in the first year of life. Pediatr Allergy Immunol 2011;22:345. 9/26/2018 14

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