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Flashcards in Qualitative Disorders of Leukocytes Deck (17)
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What is the general series of events and chemical signals involved in the immune response?

Infection/tissue damage -> release of inflammatory mediators (Toll-like recept/ligands; lipid: PAF, cytokines: IL-1, TNF, IL-6, INF-g, chemokines, complement: C3a, C5a, Kinins, coagulation factors) -> Vascular dilation, vascular permeability, emigration of leukocytes -> innate and/or adaptive immune response.


What receptors and organelles/cytostructures are required for rolling and adherence in the vasculature?

Receptors: Sialyl LeX, L-selectin, B2 integrins. Organelles/structures: plasma membrane receptors, granules containing the receptors, actin cytoskeleton & proteins.


What receptors and organelles are required for chemotaxis?

Receptors: C5a, N-formyloligopeptides, lipid compounds (LTB, PAF), G-, GM-CSF, IL-8, TNFa. Organelles: Plasma membrane, actin cytoskeleton & proteins, granules, glycolysis.


What receptors and organelles are important for ingestion and degranulation/killing?

Receptors: FcgRI, FcgRII, FcgRIII, C3bi, CR-1. Organelles: Plasma membrane, actin cytoskeleton & proteins, glycolysis. Organells specific for degranulation/killing: azurophilic and specific granules, phagolysosome formation.


How are ROS produced within the cell?

O2 is reduced to O2- or other ROS by NADPH2 and enzymes.   ROS are then held within phagolysosomes.


What are the screening tests for innate immune disorders?

1 - CBC, differential   2 - Review of morphology   3 - Bactericidal activity   4 - Chemotaxis assay   5 - Expression of CD11b/CD18   6 - NBT dye reduction or DHR oxidation


What are the clinical presentations, functional defects, and molecular defects of Leukocyte Adhesion Deficiency (LAD) I? 

Recurrent soft tissue infections - gingivitis, mucositis, periodontitis, cellulitis, abscesses, poor wound healing.   Functional defect: Neutrophilia, Decreased adherence causes a defect in movement from blood to tissues.   Molecular defect: complete or partial deficiency of CD18, resulting in a lack of expression of CD11b/CD18


What are the clinical presentations, functional defects, and molecular defects of Leukocyte Adhesion Deficiency (LAD) II? 

Recurrent infections, mental retardation, short stature, craniofacial abnormalities.   Functional defect: Neutrophilia, decreased rolling on endothelial surfaces, RBC also affected.   Molecular defect: Altered fucosylation of adhesion molecules (eg Sialyl LeX) and poor interaction with selectins, this impacts neuron development hence the severe abnormalities.


What do CD11b and CD18 function in?

CD11b and CD18 both function in tight adhesion to the endothelial cells, the phase after rolling (selectins)  and before diapedesis into the tissue.


What causes actin deficiencies/dysfunctions and what do they result in?

Actin deficiencies are often caused by defects in the actin associated proteins.  These cause defective diapedesis and poor chemotaxis. These lead to frequent and severe infections.   


What are the clinical presentations, functional defect, and molecular defect associated with Chediak-Higashi syndrome?

Oculocutaneous albinism, nystagmus, photophobia.  Recurrent infections of the skin, muc mmbr, and resp tract.   Fever, hepatosplenomegaly, hemophagocytic disorders.  Neurodegenerative disorders.  Functional defect: Neutropenia.  Giant, leaky granules in all leukocytes.   Molecular defect: Alterations in membrane fusion with formation of giant leaky granules.   CHS1 gene defects. Leads to constant collateral damage in tissues, hence neurodegeneration.


What are the clinical presentations, functional defects, and molecular defects of Myeloperoxidase Deficiency?

Generally healthy, increased fungal infections associated with diabetes.   Functional defects: Partial or complete deficiency of myeloperoxidase.   Mild defect in killing bacteria, severe defect in killing fungus (candida).   Molecular defect: Post-translational modification defect in processing protein.


What are the clinical presentations, functional defects, and molecular defects of specific granule deficiency?

Recurrent skin and deep tissue infections.   Functional defect: Decreased chemotaxis and microbicidal activity.  Neutropenia.   Molecular defect: Failure to produce specific granules or their contents.   Defect in a transcription factor (C/EBPe).  Also, do not progess to segs stage, only bands.   


What are the clinical presentations, functional defects, and molecular defects of Chronic Granulomatous Disease?

Recurrent purulent infections with bac and fungi of skin and muc mmbr, also deep infections of lung, liver, spleen, lymph nodes and bones.   Functional defect: Neutrophilia.   No toxic ROS produced, leading to inability to kill coagulase positive bac & fungi.   Molecular defect: Defects in any of four oxidase components.   Mildly x-linked, also a variant of G6PD deficiency.


What types of infections are common in phagocyte disorders?

1 - high rates of bacterial and fungal infections.  2 - Infections with atypical pathogens.   3 - CDG patients have infections with catalase positive organisms.   4 - Infections of exceptional severity.   5 - Periodontal disease in childhood.   6 - infections occuring at interface areas: skin, sinopulmonary, perirectal areas. Deep infections may also occur (abscesses).


What three categories are complement proteins grouped into and what diseases result from their deficiency?

Factors C1q, C4 and C2 - SLE, autoimmunity, and inflammatory vascular disease.   Factor C3 - recurrent bacterial infections.   Factors C5-C9 severe infections of neisseria (gonorrhea, meningitis).


Five management strategies for patients with innate immune disorders.

1 - Anticipation of infection and aggresive attempts to define the cause.   2 - Surgical procedures.   3 - Prompt initiation of broad spectrum antibiotics & switch to narrow when agent is ID'd.   4 - G-CSF in severe neutropenia.   5 - Prophylactic antibiotics for specific syndromes   Also - transplanting of hematopoietic stem cells may work, gene therapy on the horizon.