14: Inherited Immunodeficiencies Flashcards
Inherited immunodeficiencies are caused by ______.
Defects in germ-line DNA
Patients with asplenia have elevated susceptibility to _____________.
Encapsulated bacterial pathogens
What kind of infections are patients with asplenia especially susceptible to?
Septic infections since the spleen is one of the blood filters and splenic macrophages take up bacteria in the blood
T or F: Asplenia can be acquired or inherited.
T
What is the clinical intervention for asplenia?
- Vaccination for encapsulated bacterial pathogens
- Prophylactic antibiotic treatment is recommended prior to dental procedures and upon showing symptoms of respiratory infection or fever
What happens in leukocyte adhesion deficiency?
Defective CD18 causes defective migration of phagocytes into infected tissues and causes widespread infections with capsulated bacteria
What happens in chronic granulomatous disease (CGD)?
Defective NADPH oxidase prevents respiratory burst, which impairs killing of phagocytosed bacteria and leads to chronic infections and granulomas
What happens in glucose-6-phosphate dehydrogenase (G6PD) deficiency?
Defective respiratory burst, which impairs killing of phagocytosed bacteria, leading to chronic infections and sometimes anemia
What happens in myeloperoxiase deficiency?
Can’t form HOCl, which impairs killing of phagocytosed bacteria, leading to chronic bacterial and fungal infections
What happens in Chediak-Higashi syndrome?
Defect in vesicle fusion leads to impaired phagocytosis, and this causes recurrent and persistent infections and granulomas
What are neutropenias?
Disorders characterized by low numbers of granulocytes, so there is ineffective clearance of bacterial pathogens
T or F: Several primary immunodeficiencies have an associated neutropenia.
T
What is the typical clinical presentation of NK cell defects?
Typically increased incidence and severity of viral and other infections, especially varicella zoster, herpes, cytomegaloviruses, EBV, mycobacterium avium/intracellulare, and Trichophyton
In a genetic NK cell deficiency, what are some processes that can be affected?
- Formation of cytoplasmic granules
- Perforin defects
- Development in bone marrow
Genetic deficiencies in the _______ immune system can result in reduced pattern recognition by phagocytes.
Innate
What happens in NEMO deficiency?
PRRs are intact, but transcription of the genes that should be expressed following recognition is deficient. There is a genetic defect in a protein required for NFkB activity.
- Patients have recurrent bacterial and viral infections
- Patients have: deep set eyes, sparse/fine hair, missing teeth, and unusual blistering
Most Toll-Like Receptor signaling activates ______, which controls cytokine expression.
NFkB
What is the treatment for NEMO deficiency?
Biweekly injections of gamma globulin from a healthy donor or bone marrow transplant
(stem cell transplant has also shown promise)
Defects in C3 or activation of C3 are associated with _________.
Infections by encapsulated bacteria (emphasizes the role of C3b in opsonization)
What happens when you have a defect of C1, C2, or C4?
Immune complex disease – immune complexes are deposited along vasculature, which can cause inflammation (vasculitis), especially in the kidneys
What happens when you have a defect of C5-C9?
Higher susceptibility to Neisseria
What happens when you have a defect of Factor D or Factor P?
Higher susceptibility to capsulated bacteria and Neisseria but no immune-complex disease
What happens when you have a defect of Factor I?
Susceptibility to capsulated bacteria
What happens when you have defects in DAF or CD59?
Paroxymal Nocturnal Hemoglobinuria – complement-induced intravascular hemolytic anemia, red urine, and thrombosis
-Happens because there is a deficiency in the glycophosphatidylinositol tail, which interferes with MAC formation
What happens when you have defects in C1INH?
HANE – systemic edema because of overproduction of anaphylatoxins
What is the treatment for HANE?
C1INH replacement therapy
What is the clinical presentation for mannose-binding lectin (MBL) deficiency?
Patients experience recurrent severe infections
What is the treatment for paroxysmal nocturnal hemoglobinuria?
Allogenic bone marrow transplantation is curative, but C5-specific monoclonal antibody is effective at reducing the need for blood transfusions
Antibody deficiencies result in ________.
Susceptibility to extracellular bacteria, especially encapsulated bugs that are resistant to phagocytosis
What is the treatment for inherited antibody deficiencies?
Monthly injections of gamma globulin from healthy donors
What is X-linked agammaglobulinemia?
A defect in Bruton’s tyrosine kinase that causes a significant decrease in B cell development
-Patients are susceptible to extracellular bacterial pathogens and many viruses
What is pre-B cell receptor (lambda-5) deficiency?
Mutation of lambda-5 gene prevents formation of a functional surrogate light chain, so B cells can’t produce a pre-B cell receptor and undergo apoptotic death
-Patients are susceptible to both extracellular bacteria and many viral pathogens
What are the two possible causes of X-linked hyper IgM syndrome?
- Defect in T cell function
- Activation-induced cytidine deaminase (AID) deficiency (AID is required for class switching and somatic hypermutation)
X-linked hyper IgM syndrome due to defective T cell function is due to a defect in _____ expression.
CD40L
T or F: Failure to form germinal centers in secondary lymphoid tissues is characteristic of X-linked hyper IgM syndrome.
T
What is the most common primary immunodeficiency disorder?
Common Variable Immunodeficiency (CVID)
In selective IgA deficiency, ______ can be transported across mucosal epithelia and perform the function of IgA.
IgM
TAP peptide transporter deficiency results in ________.
Very low levels of MHC class I molecules and defective responses to intracellular pathogens due to CD8+ T cell deficiency; very low numbers of CD8+ T cells
What happens when you have a non-sense mutation of perforin?
You have dramatically or totally reduced CTL activity but normal numbers of CD8 T cells and CTLs are unable to induce programmed cell death of target cells
Patients with T cell defects are said to suffer from __________.
Severe Combined Immune Deficiency (SCID)
ADA deficiency and PNP deficiency both lead to _______.
Accumulation of nucleotide catabolites that are particularly toxic to developing T and B cells
What happens in bare lymphocyte syndrome?
Lack of expression of all MHC class II molecules results in an inability of CD4 T cells to be positively selected in the thymus
What is Wiskott-Aldrich syndrome?
Defect in cytoskeletal reorganization that is needed for T cells to deliver cytokines nd other signals to B cells and macrophages
What happens in common gamma chain deficiency?
Normally, the common gamma chain is the signaling component of a number of cytokine receptors that interacts with Jak3 to initiate signaling. People that fail to produce this protein can’t initiate signaling of the cytokine receptors and they have SCID.
What is Omenn syndrome?
Missense mutations that result in partially active RAG enzymes. This leads to an absence of B cells and low numbers of oligoclonal auto reactive T cells.
- Patients develop fungal, bacterial, and viral infections
- Symptoms: erythoderma, desquamation, alopecia, chronic diarrhea, failure to thrive, lymphadenopathy, and hepatosplenomegaly
What is the treatment for Omenn syndrome?
Bone marrow transplant
What happens in Complete DiGeorge Syndrome?
- Patient has absent or nonfunctional thymus, so they have very few if any T cells
- Patients develop fungal, bacterial, and viral infections typical of SCID
What is the treatment for complete digeorge syndrome?
Thymic transplant
What happens when you have a Zap-70 deficiency?
Can’t signal properly via ITAMs, so there’s an absence of CD8 T cells but normal numbers of non-functional CD4 T cells
What is the treatment for ZAP-70 deficiency?
Bone marrow transplant
What is APECED?
A deficiency of AIRE (TF that regulates expression of host-tissue specific genes by epithelial cells in the thymic medulla)
What is IPEX?
Genetic deficiency of FoxP3 expression in regulatory CD4 T cells that results in early onset autoimmunity to host tissues due to a lack of Treg cell function
How does IPEX typically present?
- Watery diarrhea
- Eczematous dermatitis
- Endocrinopathy
- Most kids also display Coombs-positive anemia, autoimmune thrombocytopenia, autoimmune neutropenia, and tubular nephropathy
What is the treatment for IPEX?
Aggressive immunosuppression and/or bone marrow transplant
What is autoimmune lymphoproliferative syndrome (ALPS)?
A genetic disease characterized by lymphadenopathy and splenomegaly that results from immune cells failing to undergo apoptotic death following an immune response
- Causes overpopulation os secondary lymphoid tissues
- Mutation prevents expression of either Fas, FasL, or caspase 10
What is the treatment for ALPS?
Immunosuppression and IVIg
