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BLOCK 2 FINAL > Immunology: Immunodeficiences > Flashcards

Immunology: Immunodeficiences Flashcards

0
Q

Asplenia

A

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

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1
Q

NK Cell Deficiency

A

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

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2
Q

Name the diseases associated with phagocyte deficiencies

A 
Leukocyte Adhesion Deficiency
Chronic Granulomatous Disease
Glucose-6-Phosphate Dehydrogenase Deficiency 
Myeloperoxidase Deficiency
Chediak-Higashi Syndrome
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3
Q

NEMO (IKKy) Deficiency

A

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

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4
Q

What susceptibilities go along with phagocyte function?

A

Chronic bacterial and fungal infections

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5
Q

Leukocyte Adhesion Deficiency

A

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

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6
Q

Chronic Granulomatous Disease (CGD)

A

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

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7
Q

Glucose-6-Phosphate Dehydrogenase Deficiency

A

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

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8
Q

Myeloperoxidase Deficiency

A

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

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9
Q

Neutropenias

A

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

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10
Q

Chediak-Higashi Syndrome

A

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!

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11
Q

What are the 3 most common types of neutropenias

A

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

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12
Q

Cyclic Neutropenia

A

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

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13
Q

Severe Congenital Neutropenia (Kostmann Syndrome)

A

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

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14
Q

Benign Chronic Neutropenia

A

low but not life-threatening neutropenia and often asymptomatic

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15
Q

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

A

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

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16
Q

C1, C2, C4 Deficiency

A

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

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17
Q

C3 Deficiency

A

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

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18
Q

C5-C9 Deficiency

A

susceptible to Neisseria; no MAC formation

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19
Q

Factor D, properdin (Factor P) Deficiency

A

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

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20
Q

Factor I Deficiency

A

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

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21
Q

DAF and CD59 Deficiency

A

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

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22
Q

C1 Inhibitor Deficiency

A

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

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23
Q

Mannose-binding Lectin (MBL) Deficiency

A

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

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24
Q

List the antibody deficiencies

A 
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)
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25
Q

X-linked agammaglobulinemnia (XLA)

A

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

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26
Q

Pre-B Cell Receptor (lambda5) Deficiency

A

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

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27
Q

Selective IgA Deficiency

A

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.

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28
Q

X-linked hyper IgM Syndrome

A

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

29
Q

Selective IgG Deficiency

A

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

30
Q

Common Variable Immunodeficiency (CVID)

A

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

31
Q

IL-12 Signaling Deficiency

A

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

32
Q

Job’s Syndrome Clinical Presentation

A 
"FATED"
coarse or leonine Facies
cold (noninflammed) staphylococcal Abscesses 
retained primary Teeth
increased IgE
Dermatologic problems (eczema)
33
Q

Job’s Syndrome (hyper IgE Syndrome)

A

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

34
Q

Name the diseases related to CD8+ T cell Deficiency

A

TAP Peptide Transporter Deficiency
CD8 Alpha Chain Defect
Non-sense Mutation of Perforin

Note: these mutations lead to viral and intracellular bacterial infection susceptibility

35
Q

TAP Peptide Transporter Deficiency

A

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

36
Q

CD8 alpha chain defect

A

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

37
Q

Non-sense mutation of perforin (Perforin Deficiency)

A

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

38
Q

Ataxia telangiectasia

A

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

39
Q

Chronic Mucocutaneous Candidiasis

A

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

40
Q

_______ T cell defects can result in SCID

A

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

41
Q

Name the immunodeficiencies that result in SCID

A 
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
42
Q

Bare Lymphocyte Syndrome (MHC Class II)

A

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

43
Q

Wiskott-Aldrich Syndrome (WAS)

A

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

44
Q

Adenosine Deaminase (ADA) or Purine Nucleotide Phosphorylase Deficiencies

A

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

45
Q

Common gamma chain deficiency

A

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

46
Q

Janus kinase 3 (Jak3) Deficiency

A

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

47
Q

CD3 Deficiency

A

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

48
Q

Thymic Aplasia

A

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

49
Q

Complete DiGeorge Syndrome

A

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

50
Q

Zap-70 Deficiency

A 
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
51
Q

Omenn Syndrome

A

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

52
Q

Name the immunodeficiencies that result in autoimmune diseases

A

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

53
Q

Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED)

A

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

54
Q

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

A

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

55
Q

Autoimmune Lymphoproliferative Syndrome (ALPS)

A

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

56
Q

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

A 
Antigenic Variation 
Antigenic Drift
Antigenic Shift 
Latency 
Superantigens
57
Q

What is antigenic variation

A

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
58
Q

What is antigenic drift

A

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
59
Q

What is antigenic shift

A

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
60
Q

Discuss Trypanosomes

A

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)

61
Q

Latency

A

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.

62
Q

What are some examples of latency

A

Herpes simplex virus
Varicella zoster (chicken pox)
Epstein-Barr virus (EBV)

Note: most of the latent virus get reactivated with stress

63
Q

Superantigen

A

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

64
Q

Reasons why the immune response cannot clear HIV

A
  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
65
Q

What does HIV encode

A

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)

66
Q

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

A

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

67
Q

Describe the process of HIV infection

A
  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
68
Q

When can you not activate macrophages?

A

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!

69
Q

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

A

IFNy: first required signal

CD40L (on the T cell) interacts with CD40 (on the macrophage) providing the second signal

70
Q

What are the two signals required for B cell activation?

A

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.

BLOCK 2 FINAL (10 decks)

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