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

3. 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

4. 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

5. 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

6. ●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 years.
(There has been increasing success with bone marrow stem cell transplant.)
Chronic granulomatous disease with nodular lesions of the face.

7. ●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.

8. ● 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.

9. 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 /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.

10. ● 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.

11. ●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.

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

13. ●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.