Immunology: Immunodeficiences

Question 0

Asplenia

Answer 0

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

Question 1

NK Cell Deficiency

Answer 1

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

Question 2

Name the diseases associated with phagocyte deficiencies

Answer 2

Leukocyte Adhesion Deficiency
Chronic Granulomatous Disease
Glucose-6-Phosphate Dehydrogenase Deficiency 
Myeloperoxidase Deficiency
Chediak-Higashi Syndrome

Question 3

NEMO (IKKy) Deficiency

Answer 3

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

Question 4

What susceptibilities go along with phagocyte function?

Answer 4

Chronic bacterial and fungal infections

Question 5

Leukocyte Adhesion Deficiency

Answer 5

defect in CD18 (an integrin adhesion molecule normally expressed by phagocytes); delayed detachment and sloughing of the umbilical cord; widespread infections with encapsulated bacteria

Question 6

Chronic Granulomatous Disease (CGD)

Answer 6

NAPDH oxidase deficiency produces no toxic oxygen intermediates; chronic bacterial and fungal infections; make granulomas more readily than normal patients

Question 7

Glucose-6-Phosphate Dehydrogenase Deficiency

Answer 7

chronic bacterial and fungal infections; similar to Chronic Granulomatous Disease; anemia induced by certain agents

Question 8

Myeloperoxidase Deficiency

Answer 8

chronic bacterial and fungal infections; similar to CGD and G6PDD; phagocytes cannot produce toxic oxygen species

Question 9

Neutropenias

Answer 9

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

Question 10

Chediak-Higashi Syndrome

Answer 10

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!

Question 11

What are the 3 most common types of neutropenias

Answer 11

Severe Congential Neutropenia (Kostmann Syndrome)
Cyclic Neutropenia
Benign Chronic Neutropenia

Question 12

Cyclic Neutropenia

Answer 12

autosomal dominant disorder with neutropenia occurring every 2-4 weeks and lasts about 1 week; ELA-2 gene defect

Question 13

Severe Congenital Neutropenia (Kostmann Syndrome)

Answer 13

autosomal recessive disorder associated with gene abnormality of granulocyte colony stimulating factor (G-CSF) or its receptor (G-CSFR)

Question 14

Benign Chronic Neutropenia

Answer 14

low but not life-threatening neutropenia and often asymptomatic

Question 15

What are the primary immunodeficiencies that have a high incidence of associated neutropenia

Answer 15

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

Question 16

C1, C2, C4 Deficiency

Answer 16

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

Question 17

C3 Deficiency

Answer 17

susceptible to encapsulated bacteria; no ability to activate any complement cascade

Question 18

C5-C9 Deficiency

Answer 18

susceptible to Neisseria; no MAC formation

Question 19

Factor D, properdin (Factor P) Deficiency

Answer 19

susceptible to encapsulated bacteria and Neisseria, but no immune-complex disease; Factor D is critical to alternative pathway

Question 20

Factor I Deficiency

Answer 20

similar to C2 deficiency because depletion of C3b; reduced cleavage of C3b or C4b with abnormally high levels of C3 convertase; susceptible to bacteria

Question 21

DAF and CD59 Deficiency

Answer 21

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

Question 22

C1 Inhibitor Deficiency

Answer 22

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

Question 23

Mannose-binding Lectin (MBL) Deficiency

Answer 23

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

Question 24

List the antibody deficiencies

Answer 24

``` 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) ```

Question 25

X-linked agammaglobulinemnia (XLA)

Answer 25

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

Question 26

Pre-B Cell Receptor (lambda5) Deficiency

Answer 26

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

Question 27

Selective IgA Deficiency

Answer 27

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.

Question 28

X-linked hyper IgM Syndrome

Answer 28

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

Question 29

Selective IgG Deficiency

Answer 29

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

Question 30

Common Variable Immunodeficiency (CVID)

Answer 30

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

Question 31

IL-12 Signaling Deficiency

Answer 31

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

Question 32

Job's Syndrome Clinical Presentation

Answer 32

``` "FATED" coarse or leonine Facies cold (noninflammed) staphylococcal Abscesses retained primary Teeth increased IgE Dermatologic problems (eczema) ```

Question 33

Job's Syndrome (hyper IgE Syndrome)

Answer 33

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

Question 34

Name the diseases related to CD8+ T cell Deficiency

Answer 34

TAP Peptide Transporter Deficiency CD8 Alpha Chain Defect Non-sense Mutation of Perforin Note: these mutations lead to viral and intracellular bacterial infection susceptibility

Question 35

TAP Peptide Transporter Deficiency

Answer 35

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

Question 36

CD8 alpha chain defect

Answer 36

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

Question 37

Non-sense mutation of perforin (Perforin Deficiency)

Answer 37

Dramatically or totally reduced CTL and NK activity Normal CD8 T cells CTLs unable to induce apoptosis to VIRAL and some intracellular pathogens

Question 38

Ataxia telangiectasia

Answer 38

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

Question 39

Chronic Mucocutaneous Candidiasis

Answer 39

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

Question 40

_______ T cell defects can result in SCID

Answer 40

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

Question 41

Name the immunodeficiencies that result in SCID

Answer 41

``` 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 ```

Question 42

Bare Lymphocyte Syndrome (MHC Class II)

Answer 42

classic MHC Class II deficiency; unable to mount CD4 T cell responses or acquired B cell responses, results in SCID

Question 43

Wiskott-Aldrich Syndrome (WAS)

Answer 43

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

Question 44

Adenosine Deaminase (ADA) or Purine Nucleotide Phosphorylase Deficiencies

Answer 44

Results in accumulation of toxic nucleotide catabolites that kills developing B and T cells; results in SCID

Question 45

Common gamma chain deficiency

Answer 45

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

Question 46

Janus kinase 3 (Jak3) Deficiency

Answer 46

similar phenotype to Common Gamma Chain Deficiency; leads to SCID; prevents signaling through cytokine receptors

Question 47

CD3 Deficiency

Answer 47

results from nonfunctional CD3 delta, epsilon, or zeta chain results in no CD4+ or CD8+ T cells -> no T cell function leads to SCID

Question 48

Thymic Aplasia

Answer 48

results in SCID phenotype; no development of T cells; absence of Thymus

Question 49

Complete DiGeorge Syndrome

Answer 49

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

Question 50

Zap-70 Deficiency

Answer 50

``` 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 ```

Question 51

Omenn Syndrome

Answer 51

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

Question 52

Name the immunodeficiencies that result in autoimmune diseases

Answer 52

Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED) Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked Syndrome (IPEX) Autoimmune Lymphoproliferative Syndrome (ALPS)

Question 53

Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED)

Answer 53

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

Question 54

Immune Dysregulation Polyendocrinopathy Enteropathy, X-linked Syndrome (IPEX)

Answer 54

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

Question 55

Autoimmune Lymphoproliferative Syndrome (ALPS)

Answer 55

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

Question 56

What are the methods of immune response evasion utilized by selected pathogens?

Answer 56

``` Antigenic Variation Antigenic Drift Antigenic Shift Latency Superantigens ```

Question 57

What is antigenic variation

Answer 57

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

Question 58

What is antigenic drift

Answer 58

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

Question 59

What is antigenic shift

Answer 59

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

Question 60

Discuss Trypanosomes

Answer 60

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)

Question 61

Latency

Answer 61

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.

Question 62

What are some examples of latency

Answer 62

Herpes simplex virus Varicella zoster (chicken pox) Epstein-Barr virus (EBV) Note: most of the latent virus get reactivated with stress

Question 63

Superantigen

Answer 63

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

Question 64

Reasons why the immune response cannot clear HIV

Answer 64

1. Antigenic variation that results because of the error rate of reverse transcriptase 2. Latency - HIV provirus integrates into host DNA and remains latent for long periods of time 3. Induction of acquired immunodeficiency

Question 65

What does HIV encode

Answer 65

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)

Question 66

How can you describe HIV virus and whats the primary host cell

Answer 66

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

Question 67

Describe the process of HIV infection

Answer 67

1. 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, 2. 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. 3. 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 4. Kills host cell at end of its replication cycle

Question 68

When can you not activate macrophages?

Answer 68

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!

Question 69

What are the two signals that macrophages require to become activated?

Answer 69

IFNy: first required signal | CD40L (on the T cell) interacts with CD40 (on the macrophage) providing the second signal

Question 70

What are the two signals required for B cell activation?

Answer 70

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.