Flashcards in Immunodeficiencies Deck (85):
Name the 2 major consequences of asplenia.
1) Increased susceptibility to encapsulated bacterial pathogens (S. pneumonia, H. influenzae, Neisseria)
2) Elevated susceptibility to septic infections by these pathogens (because spleen is one of the body’s blood filters and has macrophages that take up bacteria in the blood).
How to you help someone with asplenia not get infected?
Those without a spleen should be given vaccinations for encapsulated bacterial pathogens and begin taking antibiotics prophylacticly is they show symptoms of respiratory infection or fever.
"NK cell deficiencies" can be a result of what genetic deficiencies?
• Defective formation of cytoplasmic granules
• Defective perforin
• Defects in development of bone marrow
Those persons with NK cell deficiencies suffer from increased levels of infections by what pathogens?
1) Varcella Zoster Virus, Herpes Virus, Cytomegalovirus, Epstein-Barr Virus
2) Mycobacterium opportunistic pathogens
3) Trichophyton (fungus that leads to hair, skin, and nail infections)
What is called X-linked hypohydrotic ectodermal dysplasia and immunodeficiency known as?
What is NEMO deficiency?
a genetic defect in a protein (IKKγ or NEMO) that is required for NFkB activity (an important transcription factor for controlling cytokine expression in response to TLR signaling)
What are physical characteristics of a patient with NEMO deficiency?
• Deep-set eyes
• Sparce and/or fine hair
• Conical or missing teeth
• Skin condition that leads to blistering and changes in skin color (incontinentia pigmenti)
Those with NEMO deficiency suffer from increased rates of viral and bacterial infections, but what specific bacterial pathogen?
How do you treat someone with NEMO deficiency?
biweekly injections of gamma globulin from a healthy donor or a bone marrow transplant.
What is the genetic basis of Leukocyte Adhesion Deficiency (LAD)?
Defective CD18 (adhesion molecule) leading to defective migration of phagocytes into infected tissue
Those with LAD have an increased susceptibility to what pathogens?
Widespread infections with capsulated bacteria
What is the most telling clinical sign of LAD?
delayed detachment and sloughing of umbilical cord
What is Myeloperoxidase Deficiency?
Impaired production of HOCL by neutrophils and macrophages, so impaired killing of phagocytosed bacteria.
Those with Myeloperoxidase Deficiency have an increased susceptibility to what pathogens?
Chronic bacterial and fungal infections
What is Glucose-6-Phosphate Dehydrogenase Deficiency?
Deficiency of G6PD, so no respiratory burst, and impaired killing of phagocytosed bacteria.
Those with Glucose-6-Phosphate Dehydrogenase Deficiency have an increased susceptibility to what pathogens?
Chronic bacterial and fungal infections, with anemia being induced by some agents
What is Chronic granulomatous disease?
Defective NADPH oxidase leading to impaired killing of phagocytosed bacteria (phagocytes cannot produce O2-).
Those with Chronic granulomatous disease have an increased susceptibility to what pathogens?
Chronic bacterial and fungal infections, leading to formation of granulomas
What is Chediak-Higashi Syndrome?
Defect in vesicle fusion leading to impaired phagocytosis due to inability of endosomes to fuse with lysosomes
Those with Chediak-Higashi Syndrome have an increased susceptibility to what pathogens?
Recurrent and persistent bacterial infections, granulomas.
What are some clinical manifestations of Chediak-Higashi Syndrome?
Effects on many organs
many patients die before adulthood
What are the two major types of neutropenia?
-Severe Congenital Neutropenia (Kostmann syndrome)
What is the cause of Severe Congenital Neutropenia (Kostmann syndrome)?
Non-functional G-CSF, leading to failure of neutrophils to colonize, and low neutrophil counts (less than 500)
What is the cause of Cyclic Neutropenia?
Defect in Ela-2 (which encodes elastase) and causes cyclic episodes of neutropenia every 2-4 weeks
Those with neutropenia have an increased susceptibility to what pathogens?
Bacterial infections, even normal flora microbes
Those deficient in C1, C2, and C4 have what problems? Why?
Immune-complex disease, because no opsonization of antibody-coated antigen by classical pathway
Those deficient in C3 have what problems? Why?
increased susceptibility to encapsulated bacteria, because they cannot activate any complement cascades
Those deficient in C5-C9 have what problems? Why?
Susceptibility to Neisseria, because they cannot form MAC
Those deficient in Factor D have what problems? Why?
Susceptibility to capsulated bacteria and Neisseria, because they cannot perform the alternative pathway
Those deficient in Factor I have what problems? Why?
Susceptibility to capsulated bacteria and Neisseria, due to constant C3 convertase that uses up all of the C3 needed to start the complement cascade
Those deficient in DAF/CD59 have what problems? Why?
Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (RBC lysis) that are life threatening and cause hemolytic anemia, red urine, and thrombosis.
Missing anchor protein for:
DAF- dissociates C3 convertase enzymes
CD59- prevents C9 from joining, NO MAC
Those deficient in C1INH have what problems? Why?
HANE (edema due to too many anaphylatoxins), because you do not have the enzyme that binds to C1r/C1s and forces them to dissociate from C1q--stopping classical pathway
Those deficient in MBL have what problems? Why?
Recurrent Severe Infections (especially bacterial), because there is no activation of lectin complement pathway, acute phase response impaired
What is the genetic basis for X-linked agammaglobulinemia?
Defect in Bruton’s tyrosine Kinase, so NO signal transduction for B cell development, so few B cells
Those with X-linked agammaglobulinemia have what problems?
Increased susceptibility to extracellular bacterial pathogens and viruses
What is the genetic basis of Pre-B cell Receptor (γ5) Deficiency?
Mutation in γ5 gene (component of surrogate light chain of BCR), so developing B cells are unable to produce a pre-B cell receptor and undergo apoptosis
Those with Pre-B cell Receptor (γ5) Deficiency have what problems?
Extracellular bacteria and many viral pathogens
What are the two major genetic causes of X-linked hyper IgM syndrome?
1) CD40 Defect
2) AID defect
What is the consequence of a CD40 defect?
No 2° activation of B cells (no germinal centers in 2° LT), so express little antibodies (and ONLY IgM)
What is the consequence of an AID defect?
No isotype switching/somatic hypermutation, so have extremely high levels of IgM
What is notable about Selective IgA deficiency?
it is the most common genetic cause of antibody deficiency
What is the genetic basis of Selective IgA deficiency?
Unknown, likely heterogenous
What is the consequence of Selective IgA deficiency?
No IgA, healthy unless exposed to parasite pathogens or blood transfusion, and then they experience IgA-specific hypersensitivity after blood transfusion
What is the genetic basis of Selective IgG deficiency?
Unknown, likely heterogenous
What is the interesting about Selective IgG?
Deficiency in each IgG subtypes is possible
IgG1 most important (because it is most numerous)
IgG2 if mostly in children
IgG3 most common in adults
Those with IgG1 experience problems with what pathogens? Those with IgG2?
IgG1: bacterial and viral pathogens
IgG2: encapsulated bacteria
What is the most common cause of antibody deficiency?
Common Variable Immunodeficiency
What is the genetic basis of Common Variable Immunodeficiency?
150 primary immunodeficiencies (genetic) that lead to Hypogammaglobulinemia (reduced levels of antibodies), and don’t appear until 20s-30s
Those with Common Variable Immunodeficiency experience heightened susceptibility to what pathogens?
Recurring bacterial infections and some viral infections
Deficiencies in what two molecules can lead to decreased ability to to generate TH1-type responses?
IL-12 and IFN-γ
Those with IL-12 or IL-12 receptor deficiencies have what problems?
-Make much less IFN-gamma than normal patients
-Cannot efficiently produce TH1 T cell responses
-Are more susceptible to disseminated mycobacterial infections.
What is the genetic basis of Job's syndrome?
genetic deficiency of STAT-3 function that results in reduced production of IFN-γ by TH1 cells and neutrophils that fail to respond to chemotactic signals.
Those with Job's syndrome have what problems?
-Make much less IFN-gamma than normal patients
-Cannot efficiently produce TH1 T cell responses
-course Facies (broad nose, frontal bossing, deep set eyes, doughy skin)
-recurrent Staph Abscesses
-retained primary Teeth
-Dermatologic problems (like eczema).
What is another name for TAP Peptide Transporter Deficiency?
bare lymphocyte syndrome
How does TAP Peptide Transporter Deficiency effect patients?
Results in low levels of MHC class I and defective responses to intracellular pathogens (viral and intracellular bacteria) due to CD8+ T cell deficiency (because there are few that are positively selected in thymus).
What other deficiency has a similar phenotype to TAP Peptide Transporter Deficiency?
CD8+ Alpha Chain Defeciency
What can give you normal levels of CTLs with no CTL response? What other cell type is affected?
Nonsense Mutation of Perforin
Also affects NK cells
What is the consequence of Bare Lymphocyte Syndrome (MHC Class II)?
Lack expression of MHC class II molecules, so No CD4+ T cell responses or acquired B cell responses
What is Wiskott-Aldrich Syndrome?
Defect in cytoskeletal organization, prevents T cells from delivering effector molecules to target cells, so patients lack proper cyotkine signaling between effector T cells to B cells and macrophages
What is the effect of Adenosine Deaminase (ADA) Deficiency?
Accumulation of toxic adenosine catabolites that kills all lymphocytes during their development
What is the effect of Purine nucleotide phosphorylase deficiency?
Accumulation of toxic purine catabolites that kills all lymphocytes during their development
What is Common Gamma chain Deficiency?
γc deficiency (component of many cytokine receptors (IL-2,4,7,9,15) that interacts with JAK3.
Impaired signaling results in failure of T cells to proliferate—so no effector cells (SCID phenotype)
What deficiency gives the same phenotype as Common Gamma Chain Deficiency?
Janus Kinase 3 (JAK3) Deficiency
What is the consequence of CD3 Deficiency?
Deficiency of signal transduction unit of T cells leading to total lack of T cells and a SCID phenotype
Thymic aplasia (complete DeGeorge Syndrome) can be caused by what two means?
Small deletion of chromosome 22
Complete DeGorge is when you have absent or underdeveloped thymus
What is the consequence of Thymic aplasia (complete DeGeorge Syndrome)?
Very few, if any, T cells (SCID phenotype)
Congenital heart disease (40%)
palatal abnormalities (50%)
learning problems (90%)
mild abnormal facies
How can you treat Thymic aplasia (complete DeGeorge Syndrome)?
This can be treated with thymic transplant, but other features cannot be treated.
What is Zap-70 Deficiency?
Genetic defect that prevents expression of functional ZAP-70 (tyrosine kinase that associates with phosphorylated ITAMs during signaling via TCR
What is the phenotype of a person with Zap-70 Deficiency?
Absence of CD8+ T cells, but NORMAL numbers of non-functional CD4+ T cells.
How can you treat Zap-70 Deficiency?
Can be treated with bone marrow transplant.
What is Omenn Syndrome?
Mis-sense mutation that results in partially active RAG enzymes
What is the phenotype of a person with Omenn Syndrome?
Absence of B cells and low numbers of oligoclonal, autoreactive T cells
SCID-like phenotype, erythroderma, desquamation, alopecia, chronic diarrhea, failure to thrive lymphadenopahty, hepatosplenomegaly
How can you treat someone with Omenn Syndrome?
Can only be treated with a bone marrow transplant.
What is the genetic basis of Autoimmune Polyendocrinopathy Candidasis Ectodermal Dystrophy (APECED)?
Defect in gene that incodes AIRE (transcription factor expressed in thymic medulla), so patient cannot express host proteins on MHC Class I and II that are used for T cell negative selection in the thymus
What are physical characteristics of a person with APECED?
Polyglandular autoimmunity, total baldness, malabsorption of intestines (diarrhea), hypoarathyroidism, hypogonadism
What is the genetic basis of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome (IPEX)?
Genetic deficiency in FoxP3 of Tregs leading to Autoimmune Thrombocytopenia, Autoimmune neutropenia, Coomb’s positive anemia
What are symptoms of IPEX?
Early onset triad of:
1) Watery diarrhea
2) Eczematous dermatitis
3) Endocrinopathy (Type I diabetes)
How can you treat a patient with IPEX?
Treated with aggressive immunosuppression and/or bone marrow transplant
What is the genetic basis of Autoimmune Lymphoproliferative Syndrome (ALPS)?
Mutation prevents expression of Fas, Fas ligand, or caspase 10, so immune cells fail to undergo apoptotic death following immune response. This leads to overproduction of secondary lymphoid tissues and large numbers of CD4-/CD8- T cells
What are characteristics of a patients with ALPS?
Lymphadenopathy and splenomegaly.
Autoimmune hemolytic anemia and neutropenia, thrombocytopenia (decreased platelets)
How can you treat a patient with ALPS?
Treated with immunosuppression and IVIg
What is ataxia telangiectasia?
Inherited defect in ATM gene- DNA repair enzyme leading to:
-B cell and T cell deficiency
-Low numbers of lymphocytes (T cells) in blood and very low IgA or IgE.
What are the clinical signs of ataxia telangiectasia?
What is Chronic Mucocutanous Candidiasis?
undefined genetic defect leading to T cell dysfunction and undefined cytokine deficiency