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) • 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.

Defects in Leukocyte Function

●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

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

Defects in Leukocyte Function

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.

Disseminated Candida albicans infection in a patient with hereditary myeloperoxidase deficiency.

● 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.

Defects in Leukocyte Function

Classic atopic dermatitis-like skin lesion in an 18 year old Hyper-IgE-patient.

Defects in Leukocyte Function

●Chédiak-Higashi syndromeDefect: - 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.

Chediak-Higashi disease. Normal and affected mink

●Chédiak-Higashi syndrome

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