A White Blood Cell or Leukocyte (along with some red blood cells)

Clinical Examples of Leukocyte- Induced Injury Acute • Acute respiratory distress syndrome • Acute transplant rejection • Reperfusion injury • Septic shock • Vasculitis Chronic • Arthritis • Asthma • Atherosclerosis • Glomerulonephritis • Chronic lung disease • Chronic rejection

Leukocyte Functional Defects/Defecits ►leukocyte functional defects, both genetic and acquired, lead to increased vulnerability to infections: 1. Inadequate number 2. Inadequate functioning due to defects in: – adhesion – chemotaxis – phagocytosis / phagolysosome formation – microbicidal activity

Defects in Leukocyte Function Genetic ●Leukocyte adhesion deficiency 1 • β chain of CD11/CD18 integrins ●Leukocyte adhesion deficiency 2 • Fucosyl transferase required for synthesis of sialylated oligosaccharide (receptor for selectin) ●Chronic granulomatous disease • Decreased oxidative burst – X-linked • NADPH oxidase (membrane component) – Autosomal recessive • NADPH oxidase (cytoplasmic components) ● Myeloperoxidase deficiency • defective MPO-H2O2 system ●Chédiak-Higashi syndrome • Protein involved in organelle membrane fusion

●Chronic granulomatous disease (CGD) Defects in Leukocyte Function ●Chronic granulomatous disease (CGD) • CGD is caused by a defect or a deficiency in phagocytic NADPH oxidase, resulting in absence or inadequacy of hydrogen peroxide production. • This leads to recurrent life-threatening bacterial and fungal infections –most commonly in lungs, skin, and GI. CGD refers to the characteristic granulomas that develop in response to chronic inflammation. • median survival duration is about 20-25 years. (There has been increasing success with bone marrow stem cell transplant.) Chronic granulomatous disease with nodular lesions of the face.

●Chronic granulomatous disease (CGD) (cont.) – X-linked (60-70% of all cases; typically associated with more serious disease) – the most common molecular defect in CGD is a mutation in the CYBB (cytochrome B - b subunit, or gp91) gene. More than 350 mutations in the CYBB gene have been identified. – Autosomal recessive (20-30% of all cases) • NADPH oxidase (cytoplasmic components) ♦In general, carriers of CGD are asymptomatic. However, carriers of X-CGD have a notable incidence of discoid lupus erythematosus, photosensitivity, Raynaud phenomenon, and aphthous ulcers.

● Myeloperoxidase deficiency Defects in Leukocyte Function ● Myeloperoxidase deficiency Myeloperoxidase (MPO) catalyzes the conversion of hydrogen peroxide and chloride ions into hypochlorous acid. Hypochlorous acid is 50 times more potent in microbial killing than hydrogen peroxide. ♦ Acquired MPO deficiency -- usually partial and transient (generally resolves once the inciting condition improves). -- conditions which can lead to acquired MPO deficiency = Pb toxicity, Fe deficiency, thrombotic disease, diabetes mellitus, leukemias, some hematologic disorders, some antineoplastic drugs. ♦ Hereditary MPO deficiency -- most patients are compound heterozygotes. ◊ Incidence rate =1 in 1500 population ◊ Morbidity: -- most individuals with partial or total MPO deficiency have no increased frequency of infections, probably because MPO-independent mechanisms in the PMNs can take over. If severe infectious disease occurs, it usually is a fungal infection. These primarily occur in a patient who also has diabetes mellitus.

Defects in Leukocyte Function Disseminated Candida albicans infection in a patient with hereditary myeloperoxidase deficiency. A 52 year old female presented with a fever of 39°C, painful hyperpigmented skin lesions, malaise, sore mucosae and dysphagia of 1 week's duration. There were palpable painful large inflammatory nodules in the involved skin areas. Laboratory findings were ESR 127/132, Ht 39%, WBC 23.600/μL (neutrophils 74% with some degree of hypogranulation and vacuolation) and diffuse hypergammaglobulinemia. Bone marrow aspiration revealed hyperplasia of the granulocytic series. Despite the intensive antibiotic therapy applied, the outcome was fatal a few days following admission, in a picture of septic shock. Fungi were detected in blood cultures.

● Hyper IgE syndrome, also called Job's syndrome. Defects in Leukocyte Function ● Hyper IgE syndrome, also called Job's syndrome. Pathology: - genetic defect unknown … results in ▪ deficient chemokine expression (TGF-β, IFN-γ), ▪ decreased neutrophil and macrophage chemotaxis; ▪ markedly elevated serum IgE levels Clinical Effect: - multiple, chronic, skin and upper resp. tract infections, esp. fungal. - eczematous dermatitis - susceptible to bone fractures, other bone/facial/dental abnormalities. Classic atopic dermatitis-like skin lesion in an 18 year old Hyper-IgE-patient.

●Chédiak-Higashi syndrome Defects in Leukocyte Function ●Chédiak-Higashi syndrome Defect: - CHS gene defect results in dysfunctional intracellular protein transport. - defective synthesis and maintenance of storage/secretory granules. - microtubule assembly abnormalities Clinical Effect: [= infections + albinism + bleeding] ▪ Leukocytes – neutropenia; reduced chemotaxis response, - abnormal azurophil granules, defective degranulation (delayed and reduced killing) - frequent, severe pyogenic infections, especially skin, respiratory tract, enterocolitis. ▪ Melanocytes – defective melanosomes …. develop oculocutaneous albinism. ▪ Platelets – defective dense granules ….. develop bleeding disorder Outcome – death before age 10 without BMT.

Defects in Leukocyte Function ●Chédiak-Higashi syndrome Oculocutaneous albinism is prominent, and, together with photophobia and silvery hair, it is helpful in early diagnosis.

●Chédiak-Higashi syndrome Chediak-Higashi disease. Normal and affected mink The Chédiak-Higashi syndrome of Persian cats which includes white blood cell changes, increased susceptibility to infection, bleeding problems and haircoat paleness.