Immunology: Immunodeficiences Flashcards
Asplenia
Elevated susceptibility to encapsulated bacterial pathogens (Strep pneumonia, H. influenzae) –> especially susceptible to septic infections with these pathogens
Vaccination for encapsulated bacterial pathogens recommended
Prophylactic ABX treatment is recommended prior to dental procedures and upon showing symptoms of respiratory infection or fever
NK Cell Deficiency
Susceptibility to viral infections (especially varicella zoster, herpes virus, cytomegalovirus, and Epstein-Barr), opportunistic species of mycobacterium and Trichophyton
Defective formation of cytoplasmic granules, perforin, or development in bone marrow
Name the diseases associated with phagocyte deficiencies
Leukocyte Adhesion Deficiency Chronic Granulomatous Disease Glucose-6-Phosphate Dehydrogenase Deficiency Myeloperoxidase Deficiency Chediak-Higashi Syndrome
NEMO (IKKy) Deficiency
Defect in protein required for NFkB activity - most TLR signaling activates NFkB, which controls cytokine expression involved in innate immune responses
Increased susceptibility to recurrent bacterial and viral pathogens (e.g. Mycobacterium avum); unusual facial features, deep set eyes, sparse/fine hair, conical teeth and a skin condition with blistering and color changes
Treatment: biweekly injections of gamma globulin from healthy donor; bone marrow transplant
What susceptibilities go along with phagocyte function?
Chronic bacterial and fungal infections
Leukocyte Adhesion Deficiency
defect in CD18 (an integrin adhesion molecule normally expressed by phagocytes); delayed detachment and sloughing of the umbilical cord; widespread infections with encapsulated bacteria
Chronic Granulomatous Disease (CGD)
NAPDH oxidase deficiency produces no toxic oxygen intermediates; chronic bacterial and fungal infections; make granulomas more readily than normal patients
Glucose-6-Phosphate Dehydrogenase Deficiency
chronic bacterial and fungal infections; similar to Chronic Granulomatous Disease; anemia induced by certain agents
Myeloperoxidase Deficiency
chronic bacterial and fungal infections; similar to CGD and G6PDD; phagocytes cannot produce toxic oxygen species
Neutropenias
low number of granulocytes (neutrophil counts); susceptible to bacterial and fungal infection, including normal flora; increase in all Ab isotypes b/c recurrent infection causes continued activation of B cells
Chediak-Higashi Syndrome
Defective vesicle formation; endosomes fail to fuse with lysosomes; susceptible to recurrent bacterial infections
Presentation: albinism, recurrent pyogenic infections (Staph and Strep) and neurological disorders - Most fail to live until adulthood!
What are the 3 most common types of neutropenias
Severe Congential Neutropenia (Kostmann Syndrome)
Cyclic Neutropenia
Benign Chronic Neutropenia
Cyclic Neutropenia
autosomal dominant disorder with neutropenia occurring every 2-4 weeks and lasts about 1 week; ELA-2 gene defect
Severe Congenital Neutropenia (Kostmann Syndrome)
autosomal recessive disorder associated with gene abnormality of granulocyte colony stimulating factor (G-CSF) or its receptor (G-CSFR)
Benign Chronic Neutropenia
low but not life-threatening neutropenia and often asymptomatic
What are the primary immunodeficiencies that have a high incidence of associated neutropenia
X-linked hyper IgM syndrome
X-linked agammaglobulinemia (XLA)
WHIM Syndrome
Griselli Syndrome
Note: some of these disorders produce neutrophil-specific auto-antibodies that cause the neutropenia
C1, C2, C4 Deficiency
Immune-complex disease; small-immune complexes created by Ab binding to antigen and further opsonized by activation of classical complement cascade, promoting uptake and destructing of small immune complexes
C3 Deficiency
susceptible to encapsulated bacteria; no ability to activate any complement cascade
C5-C9 Deficiency
susceptible to Neisseria; no MAC formation
Factor D, properdin (Factor P) Deficiency
susceptible to encapsulated bacteria and Neisseria, but no immune-complex disease; Factor D is critical to alternative pathway
Factor I Deficiency
similar to C2 deficiency because depletion of C3b; reduced cleavage of C3b or C4b with abnormally high levels of C3 convertase; susceptible to bacteria
DAF and CD59 Deficiency
autoimmune like conditions including paraoxysmal nocturnal hemoglobinuria –> complement-induced intravascular hemolytic anemia (destroys own RBCs), red urine (due to hemoglobin in urine) and thrombosis
Note: CD59 and DAF are complement control proteins that interfere with MAC formation
Treatment: BM transplant and/or C5-specific mAb (eculizumab or Soliris) is effective for reducing need for blood transfusion
C1 Inhibitor Deficiency
inappropriate activation of classical complement cascade; uncontrolled cleavage of C2 allows too much vasoactive C2b; causes fluid accumulation can lead to death
Hereditary Angioneurotic Edema (HANE) d/t overproduction of anaphylatoxins
Note: C1INH binds to activated C1r:C1s forcing them to dissociate from C1 –> controls spontaneous activation of C1 that always occurs
Mannose-binding Lectin (MBL) Deficiency
MBL is a protein that binds to mannose residues on the surface of bacteria. Once bound, MBL becomes a substrate for MASP binding, resulting in activation of the lectin complement cascade
Deficiency of secreted PRR leads to increased susceptibility to severe bacterial infection due to impaired acute phase response
List the antibody deficiencies
X-linked agammaglobulinemia (XLA) Pre-B cell receptor (lambda5) deficiency X-linked hyper IgM Syndrome Selective IgA Deficiency Selective IgG Deficiency Common Variable Immunodeficiency (CVID)
X-linked agammaglobulinemnia (XLA)
mutation rendering Bruton’s Tyrosine Kinase (Btk) non-functional; no B cell development and no humoral immune system; susceptible to extracellular bacteria and some viruses; treatment with IV Ig
Pre-B Cell Receptor (lambda5) Deficiency
Defect in surrogate light chain (lambda 5 gene); apoptotic death of B cells during early stages of B cell development; susceptible to both extracellular bacteria and many viruses
Selective IgA Deficiency
one of the MOST COMMON genetic immunodeficiencies; most patients are healthy and never diagnosed (unless exposed to parasite pathogen); risk of anaphylactic reactions following blood transfusions.
X-linked hyper IgM Syndrome
caused by defect in CD40Ligand or receptor, or AID deficiency
CD40 more severe result with no fully activated B cells (cannot receive secondary activation signal). Abs will all be IgM and levels will be lower than in an immunocompetent person. Patients are suscpetible to Pneumocystis and to bacterial infections.
AID is required for class switching and somatic hypermutation. So, unable to class switch, but have fully activated B cells (still able to produce and activate effector T cells that supply second signal of activation to B and T cells) and IgM levels will be higher
Selective IgG Deficiency
IgG circulating in adult bloodstream: IgG1 > IgG2 > IgG3 > IgG4
IgG1: rare -> susceptible to many bacterial and viral pathogens; unknown genetic cause, likely heterogenous
IgG2: more common in kids -> susceptible to encapsulated bacteria; unknown genetic cause, likely heterogenous
IgG3: most common in adults
IgG4: unknown significance
Common Variable Immunodeficiency (CVID)
Most common immunodeficiency disorder; consists of a group of ~150 different disorders of unknown genetic etiology; recurring infections mainly with bacterial and viral pathogens involving ears, eyes, sinuses, nose, bronchi, lungs, skin etc
hypogammaglobulinema typical, diagnosis not until 2nd or 3rd decade of life
IL-12 Signaling Deficiency
inability to generate T-helper 1 response; make less IFNy than a normal patient; cannot effectively produce TH1 T cell response and inability to fully activate macrophages; most commonly susceptible to disseminated mycobacterial infections
Job’s Syndrome Clinical Presentation
"FATED" coarse or leonine Facies cold (noninflammed) staphylococcal Abscesses retained primary Teeth increased IgE Dermatologic problems (eczema)
Job’s Syndrome (hyper IgE Syndrome)
deficiency of STAT-3, results in reduced production of IFNy by TH1 and neutrophils that fail to respond to chemotactic signals.
Highly polarized toward TH2 phenotype –> high concentrations of IgE in blood
Name the diseases related to CD8+ T cell Deficiency
TAP Peptide Transporter Deficiency
CD8 Alpha Chain Defect
Non-sense Mutation of Perforin
Note: these mutations lead to viral and intracellular bacterial infection susceptibility
TAP Peptide Transporter Deficiency
very low levels of MHC class I molecules and defective responses to intracellular pathogens due to CD8 T cell deficiency; sometimes called bare lymphocyte syndrome; highly susceptible to VIRAL and some intracellular pathogens
CD8 alpha chain defect
very low levels of MHC class I molecules and defective responses to intracellular pathogens due to CD8 T cell deficiency; similar to TAP transporter deficiency; highly susceptible to VIRAL and some intracellular pathogens
Non-sense mutation of perforin (Perforin Deficiency)
Dramatically or totally reduced CTL and NK activity
Normal CD8 T cells
CTLs unable to induce apoptosis to VIRAL and some intracellular pathogens
Ataxia telangiectasia
defect in ATM gene (encodes DNA repair enzyme)
clinical triad of: ataxia (cerebellar defects), spider angiomas, and either IgA or IgE deficiency
some patients have B and T cell deficiencies; low lymphocytes in blood; elevated alpha-fetoprotein
Chronic Mucocutaneous Candidiasis
caused by T cell dysfunction and undefined cytokine deficiency leaving patients susceptible to Candida species (especially C. albicans); persistent superficial infections of skin, mucous membranes and nails
_______ T cell defects can result in SCID
CD4+ T cell defects can result in Severe Combined Immune Deficiency (SCID), because CD4 T cells are critical to both antibody-mediated and cell-mediated immune responses
Name the immunodeficiencies that result in SCID
Bare Lymphocyte Syndrome (MHC Class II) Wiskott-Aldrich Syndrome (WAS) Adenosine Deaminase (ADA) or Purine Nucleotide Phosphorylase Deficiencies Common Gamma Chain Deficiency Janus Kinase 3 (Jak3) Deficiency CD3 Deficiency DiGeorge Syndrome Zap 70 Deficiency Omenn Syndrome
Bare Lymphocyte Syndrome (MHC Class II)
classic MHC Class II deficiency; unable to mount CD4 T cell responses or acquired B cell responses, results in SCID
Wiskott-Aldrich Syndrome (WAS)
Defect in cytoskeletal reorganization needed for T cells to deliver cytokines and other signals to B cells and macrophages (cell cross-talk deficiency); results in SCID
Adenosine Deaminase (ADA) or Purine Nucleotide Phosphorylase Deficiencies
Results in accumulation of toxic nucleotide catabolites that kills developing B and T cells; results in SCID
Common gamma chain deficiency
prevents signaling through many cytokine receptors - especially IL-2 and IL-7; interacts with Jak3
no T cell proliferation or effector cells (i.e. you have T cells, but they can’t be activated and you don’t have any B cells)
leads to SCID
Janus kinase 3 (Jak3) Deficiency
similar phenotype to Common Gamma Chain Deficiency; leads to SCID; prevents signaling through cytokine receptors
CD3 Deficiency
results from nonfunctional CD3 delta, epsilon, or zeta chain
results in no CD4+ or CD8+ T cells -> no T cell function
leads to SCID
Thymic Aplasia
results in SCID phenotype; no development of T cells; absence of Thymus
Complete DiGeorge Syndrome
results from small deletion in chromosome 22 (CATCH22)
total absence of thymus or a non-functional thymus
few if any T cells (you would have B cells)
high susceptibility to bacterial, fungal, and viral infections; typical SCID phenotype
treatment = thymic transplant
Zap-70 Deficiency
defect in tyrosine kinase associated with ITAMs during T cell receptor signaling required for transduction through TCR TOTAL ABSENCE OF CD8 T CELLS NORMAL NUMBERS OF NON-FUNCTIONAL CD4 Only IgM SCID phenotype Treatment with bone marrow transplant
Omenn Syndrome
Immunodeficiency resulting in SCID AND autoimmune disease
Results from missense mutations making RAG genes only partially active
No B cells, low T cells (also note these T cells are autoreactive)
Develop fungal, bacterial, and viral infections typical of SCID (essentially the same phenotype as common gamma chain deficiency)
Symptoms: rashes, alopecia, chronic diarrhea, lymphadenopathy,
hepatosplenomegaly
Name the immunodeficiencies that result in autoimmune diseases
Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED)
Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked Syndrome (IPEX)
Autoimmune Lymphoproliferative Syndrome (ALPS)
Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED)
defect in autoimmune regulator (AIRE) in thymic medulla; AIRE drives expression of host proteins onto MHC I/II during negative selection of T cells
polyglandular autoimmunity that results in underproduction of hormones, total baldness, and diarrhea
Immune Dysregulation Polyendocrinopathy Enteropathy, X-linked Syndrome (IPEX)
FoxP3 expression deficiency by Tregs. Normal T and B cells.
Early onset (1st year of life) autoimmunity to a variety of host tissues due to lack of Treg function
Clinical Triad: Watery Diarrhea, Dermatitis, and Endocrinopathy (Type I Diabetes)
Kids show Coomb’s positive anemia
Autoimmune Lymphoproliferative Syndrome (ALPS)
Characterized by lymphadenopathy and splenomegaly
Mutation that results in no expression of Fas, FasL, Caspase 10, so immune cells fail to undergo apoptotic death resulting in overpopulation of secondary lymphoid tissue
Presents with autoimmune hemolytic anemia, neutropenia, and a large number of double negative T cells
Treatment: immunosuppression and IV Ig
What are the methods of immune response evasion utilized by selected pathogens?
Antigenic Variation Antigenic Drift Antigenic Shift Latency Superantigens
What is antigenic variation
Alteration of epitopes displayed by a pathogen that make the epitopes unrecognizable by an existing immune response
Example: S pneumoniae
- 84 different serotypes and each has antigenically distinct polysaccharide capsules
- infection with one serotype can lead to type-specific immunity that is protective against the same serotype, but does not protect against another serotype of the same organism
- End Result: same organism can cause disease in the same host many times
What is antigenic drift
Introduction of point mutations that result in minor alterations of the antigenicity of a particular protein
Example: Influenza
- Point mutations in genes encoding hemagglutinin and neuramindase
- End Result: people that were immune to the old variant of the virus are susceptible to the new variant. Since there is usually considerable cross-reactivity (Ab and T cells) between the old and new variant, most of the population has some level of immunity; therefore, symptoms associated with the new variant are mild
What is antigenic shift
Reassortment of genes that results in major changes in the antigenicity of a given protein
Example: Influenza
- reassortment of the segemented negative-strand RNA genome (and related animal influenza virus) during co-infection of an animal host. Leads to major changes int eh hemagglutinin protein on the surface of the virus
- End Result: resulting variant of virus is recognized very poorly, or not at all, by responses made against the old variant; therefore, most people are highly susceptible and severe infection results
Discuss Trypanosomes
Example of antigenic shift
Insect-borne protozoa that replicate in extracellular tissue spaces in the body and cause sleeping sickness
Coated with variant-specific glycoprotein (VSG)
Infected hosts produce a potent anti-VSG antibody response that rapidly clears most of the parasites. However, trypanosomes have many different VSG genes that each encode a VSG protein that is antigenically distinct. At least a few of the parasites that express different VSGs can escape the immune response, replicate rapidly, and cause a recurrence of disease.
End Result: chronic cycle of immune complex clearance leads to damage of host tissues, including neurological damage, and eventually resulting in coma (sleeping sickness)
Latency
a state in the life cycle of some viruses during which they do not replicate and remain “hidden” from the immune system. Usually, the viral genome is integrated into the host cell DNA.
What are some examples of latency
Herpes simplex virus
Varicella zoster (chicken pox)
Epstein-Barr virus (EBV)
Note: most of the latent virus get reactivated with stress
Superantigen
molecules that stimulate a subset of CD4 T cells by simultaneously binding to MHC II molecules and the B-chain of the TCR; these binding interactions are not specific interactions
initiates massive production of cytokines, which results in systemic toxicity and/or suppression of immune responsiveness
Reasons why the immune response cannot clear HIV
- Antigenic variation that results because of the error rate of reverse transcriptase
- Latency - HIV provirus integrates into host DNA and remains latent for long periods of time
- Induction of acquired immunodeficiency
What does HIV encode
Lentivirus (a type of retrovirus) that encodes a reverse transcriptase enzyme, integrase protein, and two surface exposed proteins (the surface unit gp160 and the transmembrane protein gp41)
How can you describe HIV virus and whats the primary host cell
Cytopathic - at the end of its replication cycle it kills the host cell. Ultimately because its primary host cells are CD4 T cells, CD4 cells are depleted
Describe the process of HIV infection
- The envelope complex of HIV (gp120:gp41) binds with high affinity to CD4 molecules, which are expressed on CD4 T cells, as well as on macrophages and dendritic cells,
- Once HIV has bound CD4, it must interact with a co-receptor on the host cell (a chemokine receptor) to gain entry into the cell. The viral genome, reverse transcriptase, and integrase are dumped into the cytoplasm of the cell.
- Reverse transcriptase copies the viral RNA to create a double stranded provirus that is then integrated into host cell DNA. The reverse transcriptase has no proofreading ability, which gives rise to high rates of antigenic variation
- Kills host cell at end of its replication cycle
When can you not activate macrophages?
CD40 Deficiency - often diagnosed with systemic infections such as Mycobacterium intracellularae
IFN gamma or IFN gamma receptor Deficiency
However, with AID you will have granulomas!
What are the two signals that macrophages require to become activated?
IFNy: first required signal
CD40L (on the T cell) interacts with CD40 (on the macrophage) providing the second signal
What are the two signals required for B cell activation?
1) Recognition of their cognate antigenic determinant through their BCR
2) Activation stimuli from helper T cells that consist of CD40 ligand of the T cell binding to CD40 on the surface of the B cell, and cytokine signals by the helper T cell.
When a helper T cell recognizes its cognate peptide determinant bound to MHC Class II on the surface of that B cell, it will perform its effector function and supply the CD40 ligand and cytokine signals resulting in B cell activation.
