Week 14 - Non-Malignant Leukocyte Disorders (PDF)

NON-MALIGNANT LEUKOCYTE DISORDERS Not caused by clonal or neoplastic changes in hematopoietic precursor cells Causes can be genetic or acquired and involve one or more lineages: neutrophil, lymphocyte, monocyte, eosinophil, and basophil, affecting the number of circulating cells, morpholog...

NON-MALIGNANT LEUKOCYTE DISORDERS Not caused by clonal or neoplastic changes in hematopoietic precursor cells Causes can be genetic or acquired and involve one or more lineages: neutrophil, lymphocyte, monocyte, eosinophil, and basophil, affecting the number of circulating cells, morphology, or both Many of these disorders are associated with significant clinical manifestations, although some are benign in nature  TYPES:  QUALITATIVE NON-MALIGNANT  QUANTITATIVE NON-MALIGNANT/REACTIVE STATES QUALITATIVE NON-MALIGNANT LEUKOCYTE DISORDERS  MORPHOLOGICAL ABNORMALITIES INVOLVING NEUTROPHILS DEFECTIVE LEUKOCYTE MOTILITY/MOVEMENT DEFECTIVE RESPIRATORY BURST LYSOSOMAL STORAGE DISORDERS INHERITED DISORDERS OF LYMPHOCYTES MORPHOLOGICAL ABNORMALITIES INVOLVING NEUTROPHILS HYPERSEGMENTATION ALDER-REILLY ANOMALY MAY-HEGGLIN ANOMALY CHEDIAK-HIGASHI SYNDROME PELGER-HUET ANOMALY PSEUDO/ACQUIRED PELGER-HUET PELGER-HUET ANOMALY (PHA)  Autosomal dominant disorder characterized by decreased nuclear segmentation and distinctive coarse chromatin clumping pattern  Affects all leukocytes, although morphologic changes are most obvious in mature neutrophils  Mutations in the lamin B-receptor gene  The lamin B receptor is an inner nuclear membrane protein that combines β- type lamins and heterochromatin and plays a major role in leukocyte nuclear shape changes that occur during normal maturation  TYPES:  HETEROZYGOUS PHA  normal individuals, pince-nez appearance of the nucleus  HOMOZYGOUS PHA  cognitive impairment, heart defects, and skeletal abnormalities may occur; single nuclei ALDER-REILLY ANOMALY  Is a rare inherited disorder characterized by granulocytes (monocytes and lymphocytes less often) with large, darkly staining metachromatic cytoplasmic granules  AR anomaly was initially reported in patients with gargoylism; however, it can be seen in otherwise healthy individuals  Granulations are also seen in mucopolysaccharidoses (MPSs) MAY-HEGGLIN ANOMALY  A rare, autosomal dominant disorder characterized by variable thrombocytopenia, giant platelets, and large Dohle body-like inclusions in neutrophils, eosinophils, basophils, and monocytes  Caused by a mutation in the MYH9 gene with disordered production of myosin heavy chain type IIA, which affects megakaryocyte maturation and platelet fragmentation CHEDIAK-HIGASHI SYNDROME A rare autosomal recessive disease of immune dysregulation Mutation in the CHS1 LYST gene Many types of cells in the body are affected and exhibit abnormally large lysosomes, which contain fused dysfunctional granules Clinical manifestations begin in infancy with partial albinism and severe recurrent life- threatening bacterial infections Patients often have bleeding issues as a result of abnormal dense granules in platelets; death occurs before the age of 10 years MORPHOLOGICAL ABNORMALITIES INVOLVING NEUTROPHILS DEFECTS IN MOTILITY/MOVEMENT  JOB’S SYNDROME  LAZY LEUKOCYTE SYNDROME  LEUKOCYTE ADHESION DISORDERS (LADs)  WHIM SYNDROME JOB’S SYNDROME Normal random movement ; abnormal CHEMOTACTIC/DIRECTIONAL MOTILITY Patient suffer from persistent boils and recurrent “cold” staphylococcal abscesses Associated with increased IgE LAZY-LEUKOCYTE SYNDROME  Abnormal random and chemotactic movement Cells failed to respond to inflammatory stimuli but have normal phagocytic and bactericidal activity LEUKOCYTE ADHESION DISORDERS  (LADs) Are rare autosomal recessive inherited conditions resulting in the inability of neutrophils and monocytes to move from circulation to the site of inflammation (called extravasation) Consequences of these disorders are recurrent severe bacterial and fungal infections Hematopoietic stem cell transplant is the only curative treatment TYPES: LAD I, II, III, others (Shwachman-Bodian Diamond syndrome) LEUKOCYTE ADHESION DISORDERS  LAD I (LADs)  Mutation in the ITGB2 gene ; gene that encodes CD18 subunit of b2 integrins, resulting in either a decreased or truncated form of the β2integrin, which is necessary for adhesion to endothelial cells, recognition of bacteria, and outside-in signaling  Shortly after birth, patients suffer from recurrent infections, often affecting skin and mucosal infections  Lymphadenopathy, splenomegaly, and neutrophilia are common findings  LAD II  Mutation in the SLC35C1 gene ; leukocytes have normal β2 integrins  Defective fucose transporter and selectin synthesis  Patients have recurring infections, neutrophilia, growth retardation, a coarse face, and other physical deformities  LAD III  Caused by mutations in Kindlin-3 ; Kindlin-3 protein along with talin are required for activation of β integrin and leukocyte rolling  Leukocytes and platelets have normal expression of integrins; however, there is failure in response to external signals that normally results in leukocyte activation  LAD III patients experience a mild LAD I-like immunodeficiency with recurrent infections  Additionally, there is decreased platelet glycoprotein IIb/IIIa, resulting in bleeding WHIM SYNDROME  WHIM  warts, hypogammaglobulinemia, infections, and myelokathexis syndrome  Defect in intrinsic and innate immunity  Mutations in the CXCR4 gene  CXCR4 protein regulates movement of white blood cells between the bone marrow and peripheral blood  Neutrophils accumulate in the bone marrow (myelokathexis), which results in low numbers of circulating neutrophils  In addition to neutropenia, lymphopenia, monocytopenia, and hypogammaglobulinemia are present; as a result, patients experience recurrent bacterial infections and are highly susceptible to human papillomavirus (HPV) infection, which leads to warts DEFECTIVE RESPIRATORY BURST CHRONIC GRANULOMATOUS DISEASE (CGD) CONGENITAL C3 DEFICIENCY G-6PD DEFICIENCY MYELOPEROXIDASE (MPO) DEFICIENCY  CHRONIC GRANULOMATOUS DISEASE (CGD) A rare condition caused by the decreased ability of neutrophils to undergoa respiratory burst after phagocytosis of foreign organisms  Can be X-linked recessive (60%) or autosomal recessive (40%)  Caused by mutations in genes responsible for proteins that make up the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NADPH oxidase deficiency)  Patients experience life-threatening catalase-positive bacterial and fungal infections  DETECTION OF RESPIRATORY BURST  Chemiluminescense  uses dihydrorhodamine to measure intracellular production of reactive oxygen species  Nitroblue  NORMAL tetrazolium PATIENTS:(NBT) test REDUCED NBT of respiratory  because NBT is a yellow, of water-soluble the dye generation burst (+BLUE FORMAZAN)  PATIENTS WITH CGD: UNREDUCED (COLORLESS- YELLOW) CONGENITAL C3 DEFICIENCY  Autosomal recessive  Heterozygous: Carriers have half the normal C3 activity (adequate for disease resistance)  Homozygous: Repeated severe infections with encapsulated bacteria which are poorly recognized and inefficiently phagocytized because of failure of G-6-PD opsonisation by C3 DEFICIENCY  Absence affect the HEXOSE MONOPHOSPHATE SHUNT  Leukocytes are unable to produce a respiratory burst, resulting in a DEFECTIVE BACTERICIDAL ACTIVITY  G6PD is needed for the production of NADPH oxidase MYELOPEROXIDASE (MPO) DEFICIENCY  Autosomal recessive ; also known as ALIUS-GRIGNASHI ANOMALY  MPO is low or absent in neutrophils and monocytes but not in eosinophils  Absence of MPO slows down bactericidal killing LYSOSOMAL STORAGE DISEASES (LSDs)  Are a group of more than 50 inherited enzyme deficiencies resulting from mutations in genes that code for the production of lysosomal enzymes  The result is flawed degradation of phagocytized material and buildup of undigested substrates within lysosomes  This causes cell dysfunction, cell death, and a range of clinical symptoms; all cells containing lysosomes can be affected  LSDs are classified according to the underdegraded macromolecule that accumulates in the cell  EXAMPLES:  LIPID STORAGE DISEASE/SPHINGOLIPIDOSES  MUCOPOLYSACCHARIDOSES LIPID STORAGE DISEASES/SPHINGOLIPIDOSES Are qualitative disorders involving monocytes and macrophages The macrophages are particularly prone to accumulate undegraded lipid products, which subsequently leads to an expansion of the reticuloendothelial tissue EXAMPLES:  GAUCHER’S DISEASE  NIEMANN-PICK’S DISEASE GAUCHER’S DISEASE  Most common of the lysosomal lipid storage diseases ; at least 1 in 17 Ashkenazi Jews are carriers  It is an autosomal recessive disorder caused by a defect or deficiency in the catabolic enzyme beta-glucocerebrosidase  Accumulation in sphingolipid glucocerebroside in macrophages throughout the body, including osteoclasts in bone and microglia in the brain  Bone marrow replacement by Gaucher cells contribute to anemia and thrombocytopenia  Pseudo-Gaucher cells can be found in bone marrow of some patients with thalassemia, chronic myeloid leukemia, acute lymphoblastic leukemia, non- Hodgkin lymphoma, and plasma cell neoplasms GAUCHER’S DISEASE NIEMANN-PICK’S DISEASE  Characterized by accumulation of sphingomyelin in cellular lysosomes in the liver, spleen, and lungs  Deficiency in the enzyme acid sphingomyelinase (ASM)  Associated with foam cells and sea-blue histiocytes in the bone marrow  TYPES:  TYPE A NP  TYPE B NP  TYPE C NP  TYPE A  Acute neuronopathic form ; affects mostly Eastern European Jews  7-8 x 10 9/L  Acute infectious—bacterial, some viral, fungal, parasitic  Drugs, toxins, metabolic—corticosteroids, growth factors, uremia, Ketoacidosis  Tissue necrosis—burns, trauma, MI, RBC hemolysis  Physiologic—stress, exercise, smoking, pregnancy  Neoplastic—carcinomas, sarcomas, myeloproliferative disorders NEUTROPENIA  Drugs—cancer chemotherapy, chloramphenicol, sulfas/other antibiotics, Absolute count: 0.3x109/L  Allergic—food, drugs, foreign proteins  Infectious—variola, varicella  Chronic hemolytic anemia—especially post splenectomy  Inflammatory—collagen vascular disease, ulcerative colitis MONOCYTOSIS  Infectious—tuberculosis, subacute bacterial endocarditis, syphilis, Absolute count: >0.9x109/L protozoan, rickettsial  Recovery from neutropenia  Hematologic—leukemias, myeloproliferative disorders, lymphomas, multiplemyeloma  Inflammatory—collagen vascular disease, chronic ulcerative colitis, sprue, myositis, polyarteritis, temporal arteritis  Others—solid tumor, immune thrombocytopenic purpura, sarcoidosis LYMPHOCYTOSIS  Infectious—many viral, pertussis, tuberculosis, toxoplasmosis, Absolute lymphocyte count rickettsial in:  Chronic inflammatory—ulcerative colitis, Crohn’s  Adults: >4.0x109/L  Immune mediated—drug sensitivity, vasculitis, graft rejection,  infants and young Graves’, Sjögren’s children:  Hematologic—ALL, CLL, lymphoma EN D