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I9 - Primary Immunodeficiencies

Terms in this set (33)

Table of Primary Immunodeficiencies
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Defects Impacting Development - Overview
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Common γ Chain
Protein chain that is the signaling component of several different cytokine receptors, including those or IL-2,4,7,9,15,21
- different from γ-Chain associated with Fc receptors
- Interacts with Protein kinase Jak3 to induce signaling from receptor when a cytokine binds
Common site of genetic mutations in X-Chromosome, defects can result in SCID
IL2 Cytokine Family
IL2
IL4
IL7
IL9
IL15
IL21
Severe Combined Immune Deficiency (SCID)
Patients who make neither T-Cell dependent antibody responses nor Cell-Mediated immune responses, typically the result of genetic defects that lead to T-Cell deficiencies. Fatal in childhood if not treated.
Bare Lymphocyte Syndromes
Genetically determined diseases in which either MHC I or MHC II molecules are not expressed on cells. Can be caused by various different regulatory gene defects, and their effect is severe immunodeficiency
- Type I Defect
- Type II Defect
Type I Bare Lymphocyte Syndrome
Defect in 1 of 2 genes encoding TAP peptide transporter. Impedes binding of peptides by MHC I, leading to low abundance of MHC I on cell surface.
--> Selective loss of CD8 T-Cells
- less severe than the SCID caused by MHC II BLS
Type II Bare Lymphocyte Syndrome
Defect in multiple genes, esp defects in transcriptional regulators essential for expression of MHC II Loci. CD4 T-Cells fail to develop, compromising all aspects of adaptive immunity
- homozygous defect in any of 4 proteins causes the deficiency: Class II Transactivator (CIITA), and 3 different components of RFX (transcriptional complex that binds promoter of MHC II genes)
X-Linked Agammaglobulinemia (XLA)
Genetic disorder in which B-Cell development is arrested at the Pre-B Cell Stage and neither mature B-Cells nor antibodies are formed. Disease is due to a defect in the gene coding for protein tyrosine kinase Btk = Intracellular signals cannot be generated in the cell.
X-lined gene = Mostly males affected.
Hyper-IgM (HIGM) Syndrome
X-linked:
- CD40L
- NEMO (IKK)
Autosomal:
- CD40
- AID
- UNG
B cell intrinsic:
- AID & UNG mutations only effect B cells
Hyper-IgM (HIGM) Syndrome: X-Linked
Defect in genes for CD40L or NEMO (IKK). No specific antibody is made against T-Cell dependent antigens. IgG, IgA, and IgE levels extremely low, and IgM high. No germinal centers. Patients inherently susceptible to infection with pyogenic bacteria, but infections may be prevented by regular injections of gamma globulin and cleared by abx when they do occur.
4 Types of Hyper IgM syndrome
1.) X-Linked (CD40L, NEMO)
2.) CD40
3.) B-Cell intrinsic Hyper IgM Syndromes, or CVIDs (AID, UNG, TACI, CD19, ICOS)
4.) Mutated genes not known IgA deficiency (one of most common: 1/600)
CD40 Hyper IgM Syndrome
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B-Cell intrinsic Hyper IgM Syndromes, or CVIDs
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Hyper IgM Syndrome - IgA Deficiency
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NEMO (IKKγ) Defect
Lack one of the subunits of IKK = impaired activation of NFkB (transcription factor for cytokines), etc.)
- Susceptible to bacterial infection because macrophage activation via TLR4 signaling is inefficient
- Abnormalities in tissue development.
- Can't prevent apoptosis
Neutrophil Deficiencies
1.) Leukocyte Adhesion Deficiency
2.) Chronic Granulomatous Disease (CGD)
3.) G6P Dehydrogenase Deficiency (resistant to malaria)
4.) Myeloperoxidase (MPO) Deficiency
5.) Chedial-Higashi Syndrome
Leukocyte Adhesion Deficiency
Defective CD18 (cell adhesion molecule)
- Defective migration of phagocytes into infected tissues
- Widespread infections with capsulated bacteria
Chronic Granulomatous Disease (CGD)
Defective NADPH Oxidase, Phagocytes cannot produce O2-
- Impaired killing of Phagocytosed bacteria
- Chronic bacterial infections. Granulomas
[Memory device: Granny is an old religious lady. She is "anti-Fag" (no phagocytosis) and using words like that she is a NAsty, Damn Properly Hurtful Old woman (NADP Oxidase). Also old grannies love cats, so if she lives with you you are more susceptible to a cat-infestation (catalase + bacteria)]
G-6-P Dehydrogenase Deficiency
Deficiency of G6P Dehydrogenase, Defective respiratory burst
- Impaired killing of phagocytosed bacteria
- Chronic bacterial and fungal infections
Anemia is induced by certain agents
Myeloperoxidase Deficiency
Deficiency of myeloperoxidase in neutrophil granules and macrophage lysosomes and impaired production of toxic oxygen species.
- Impaired killing of phagocytosed bacteria
- Chronic bacterial and fungal infections
Chediak-Higashi Syndrome
Defect in vesicle fusion
- Impaired phagocytosis due to inability of endosomes to fuse with lysosomes
- Recurrent and persistent bacterial infections. Granulomas. Effects on many organs
Silvery-White Hair
NADPH Oxidase
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IFN-γ Receptor Deficiency
General name for a genetically determined deficiency caused by lack of or low levels of the IFN-γ Receptor on macrophages and monocytes, and thus a deficiency in their function. The disease is characterized by an inability to clear intracellular bacteria, especially mycobacteria.
Complement Deficiencies
1.) C1, C2, C4
2.) C3
3.) C5-C9
4.) Factor D, Properdin (Factor P)
5.) Factor I
6.) DAF, CD59
C1, C2, C4 Deficiency
Immuno-complex disease
C3 Deficiency
Susceptibility to capsulated bacteria
C5-C9 Deficiency
Only effect is susceptibility to Neisseria
Factor D, Properdin (Factor P) Deficiency
Susceptibility to capsulated bacteria and Neisseria, but no immune-complex disease
Factor I Deficiency
Similar to deficiency of C3 (susceptibility to capsulated bacteria)
DAF, CD59 Deficiency
Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria
Paroxysmal Noctural Hemoglobinuria: DAF Deficiency
DAF inactivates C3 Convertase
DAF is one of the main proteins that protect blood cells from destruction; it disrupts formation of C3-convertase, which binds the membrane attack complex (MAC) and prevents C9 from binding to the cell. (and thus prevents formation of holes in body's own cells by MAC when it is released to attack pathogens)
Paroxysmal Noctural Hemoglobinuria: CD59 Deficiency
CD59 prevents pore formation on human cells (e.g. by the Membrane Attack Complex (MAC) when it is released to attack pathogens)
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