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FMS > FMS Week 10: Primary Immunodeficiency > Flashcards

FMS Week 10: Primary Immunodeficiency Flashcards

1
Q

Main Characteristics of Primary Immunodeficiency Disease

3 Listed

A
  • Primary (congenital)
  • Group of highly variable diseases
  • Almost always a genetic defect
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2
Q

Primary Immunodeficiency Disease Primary (Congenital)

A
  • Mutation/defect is present at birth perinatally
  • Not caused by damage to the immune system (secondary)
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3
Q

Primary Immunodeficiency

A

Mutation/defect is present at birth

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4
Q

Secondary immunodeficiency

A

Not caused by damage to the Immune system

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5
Q

Primary Immunodeficiency highly variable disease

2 Listed

A
  • time of manifestation ranges from birth to never
  • Severity ranges from mild/no known symptoms to fatal
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6
Q

Primary Immunodeficiency Disease is almost always a genetic defect because?

A
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7
Q

How many Primary Immunodeficiency Diseases are there?

A

>200 distinct Primary Immunodeficiency Diseases

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8
Q

Diagnosis of Primary Immunodeficiency Diseases

2 Listed

A
  • recurrent or severe infections are usually the first sign of a possible primary immunodeficiency disease
  • Infections at multiple sites, multiple pathogens (including normally avirulent)
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9
Q

Primary Immunodeficiency Diseases are associated with unexpected pathology such as

3 Listed

A
  • Autoimmune diseases
  • Cancer
  • Allergy
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10
Q

Primary Immunodeficiency Diseases: Defects of innate immunity

4 Listed

A
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11
Q

Primary Immunodeficiency Diseases: Defects of lymphocyte Maturation

5 Listed

A
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12
Q

Primary Immunodeficiency Diseases: Defects of lymphocyte Activation

4 Listed

A
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13
Q

Primary Immunodeficiency Diseases: Other genetic disease with lymphocyte abnormalities

A
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14
Q

Inheritance of Primary Immunodeficiency Diseases

2 Distinct Patterns

A
  • Autosomal Recessive Inheritance (requires 2 defective genes)
  • X-linked Recessive
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15
Q

Primary Immunodeficiency Diseases: Autosomal Recessive Inheritance Pattern

2 Listed

A
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16
Q

Primary Immunodeficiency Diseases: X-Linked Recessive Inheritance Pattern

4 Listed

A
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17
Q

Defects in Lymphocyte Maturation Disease Examples

5 Listed

A
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18
Q

Combines Immunodeficiency Syndromes occur in 1/? live births

A

1/58,000 live births

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19
Q

Mutations in genes whose products are crucial for the development and function of B and T cells may also affect…

A

NK cells

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20
Q

Disorders arising from disturbances in the development of B and T cells may also involve?

A

Natural Killer (NK) Cells

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21
Q

Primary Immunodeficiency Diseases can be “Severe” in that they

A

They lead to death from overwhelming infection, usually in the first year of life

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22
Q

Since 2010 90% of newborns in the U.S> are screened for?

A

SCID

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23
Q

SCID Patient Presentations

5 Listed

A
  • Severe infections
  • Lymphopenia
  • Chronic Diarrhea
  • Adverse reactions to live vaccines
  • recurrent fevers
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24
Q

Treatment of Combined Immunodeficiency Syndromes

A

Hematopoietic cell transplantation (HCT)

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25
Q

Combined Immunodeficiency Syndromes Prognosis

A

Fatal in the first year of life if not treated, best prognosis is in patients receiving HCT before 3.5 months of age with no infections

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26
Q

T Cell Receptor Excision Circles are?

A
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27
Q

TRECs Properties

4 Listed

A
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28
Q

Patients with SCID will not have mature T cells so they will not have _________

A

TRECs in the blood

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29
Q

X-Linked Severe Combined Immunodeficiency Disease: what type of mutation is most common?

A

99% of X-linked SCID are caused by γc Mutations

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30
Q

X-linked SCID prognosis

A

Fatal in the first year or 2 of life if not treated

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31
Q

X-linked SCID are symptomatic/asymptomatic at birth

A

Asymptomatic at birth and time of testing

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32
Q

X-linked SCID: undiagnosed patients present in the first year with?

5 Listed

A
  • Recurrent opportunistic infections
  • Chronic diarrhea
  • Thrush
  • Otitis media
  • Failure to thrive
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33
Q

γc deficiency =

A

X-linked Severe Combined Immunodeficiency

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34
Q

γc is shared among many?

A

Cytokine receptors

  • IL-2
  • IL-4
  • IL-7
  • IL-9
  • IL-15
  • IL-21
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35
Q

IL-7 is required for?

A

T cell development and differentiation

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36
Q

IL-7 is produced in the ________ and signals through the _________ receptor to induce _______________

A
  • Thymus
  • IL7R/γc
  • proliferation of pro-T cells
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37
Q

With γc deficiency, the effect on B cells is?

A
  • B cell number will be normal but serum Ig will be low because there are no CD4+ T cells to stimulate B cells
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38
Q

Autosomal Severe Combined Immunodeficiency: mutations in nucleotide salvage pathway Percentages

A
  • ~30% of autosomal SCID are caused by mutations in the gene coding for adenosine deaminase (ADA) enzyme
  • 1% of all SCID is caused by a mutation in Purine Nucleotide Phosphorylase (PNP) enzyme
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39
Q

ADA and PNP are both involved in?

A

Converting toxic deoxyadenosine (a byproduct of breakdown and synthesis of DNA) to non-toxic byproducts that can be salvaged for DNA synthesis or removed as waste products

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40
Q

Deficiency in ADA or PNP causes?

A

Build up of toxic deoxyadenosine

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41
Q

Treatment for ADA or PNP SCID

2 Listed

A
  • Hematopoietic Cell Transplant
  • Enzyme replacement therapy (weekly intramuscular injection)
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42
Q

ADA AKA

A

Adenosine Deaminase Enzyme (ADA)

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43
Q

PNP AKA

A

Purine Nucleotide Phosphorylase (PNP)

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44
Q

ADA and PNP deficiency toxic buildup of deoxyadenosine causes

2 Listed

A
  • Decreased DNA synthesis
  • Decreased Lymphocytes
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45
Q

RAG1 and RAG2 are?

A

proteins that are involved in VDJ recombination

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46
Q

Without RAG1 and RAG2 functionality

3 Listed

A
  • There will be no B or T cells because the cells would not be able to make it past checkpoints early in development
  • Pro-Pre checkpoint
  • Pro B & T cells need to undergo VDJ recombination which involves RAG1 and RAG2 proteins
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47
Q

For Survival Pre-B cells require:

4 Listed

A
  • Successfully rearranged H chain
  • Association with surrogate light chains
  • Association with Ig-signaling molecules
  • Basal signaling
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48
Q

Btk Deficiency: X-linked agammaglobulinemia

A

can’t get mature B cells

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49
Q

DiGeorge Syndrome caused by

2 Listed

A
  • deletion in chromosome 22q11.2
  • resulting in abnormal embryonic development of the pharyngeal pouch system
50
Q

Functional Defect in DiGeorge Syndrome

A

Rudimentary or absent thymus

51
Q

The consequence of DiGeorge Syndrome

2 Listed

A
  • Decreased T cells
  • Normal B cells but normal or reduced serum Ig (SCID)
52
Q

Clinical Aspects of DiGeorge

5 Listed

A
  • Rudimentary or absent thymus
  • Cardiac Anomalies
  • Hypocalcemia (from parathyroid hypoplasia)
  • Palatal defects
  • Gastrointestinal defects
53
Q

Treatment of DiGeorge Syndrome

A
  • Hematopoietic Cell Transplant (does not fully restore T cell repertoire but does provide adequate immune function)
54
Q

Prognosis of DiGeorge Syndrome

A

Median survival with transplant is 5 years (oldest survivors are in their 20s)

55
Q

Examples of defects of lymphocyte activation

5 Listed

A
  • Defects in TCR complex signaling: MHC Class II deficiency
  • Common Variable Immunodeficiency
  • AID mutations (autosomal hyper-IgM syndrome)
  • CD40 Ligand mutations (X-linked hyper-IgM syndrome)
  • Selective Ig isotype defects
56
Q

Common Variable Immunodeficiency is not a?

A

Not a single disease

57
Q

Common Variable Immunodeficiency Prevalance

A

1/25,000

58
Q

Common Variable Immunodeficiency is a Collection of?

A

Collection of hypogammaglobulinemia syndromes

59
Q

hypogammaglobulinemia syndromes are resulting from

A

many genetic defects

60
Q

Common Variable Immunodeficiency: Variable because?

5 Listed

A

Variable - heterogeneous clinical manifestations

  • Recurrent Infections
  • Chronic Lung Disease
  • Autoimmune Disorders
  • Gastrointestinal Disease
  • Susceptibility to lymphomas
61
Q

Common Variable Immunodeficiency Age of diagnosis

2 Listed

A
  • sometimes diagnosed in childhood, but more often after puberty (20-45 years is the most common age)
  • Often diagnosis is delayed (5-7 years after symptoms present)
62
Q

Common Variable Immunodeficiency: Specific Gene Defect

2 Listed

A
  • the specific molecular defect is known only for a small subset of patients
  • likely results from a number of different gene defects
63
Q

Common Variable Immunodeficiency: Consequence

A

impaired B cell differentiation with hypogammaglobulinemia

64
Q

Common Variable Immunodeficiency: Treatment

A

IVIG to replace low serum Ig

65
Q

Hyper IgM Syndromes prevalence

A

Rare: 1 / 1,000,000

66
Q

Hyper IgM Syndromes different mutations Examples

3 Listed

A
  • Activation-induced deaminase (AID)
  • CD40L
  • CD40
67
Q

AID Inheritance Pattern

A

Autosomal Recessive

68
Q

CD40L Inheritance Pattern

A

X-Linked Recessive

69
Q

CD40 Inheritance Pattern

A

Autosomal Recessive

70
Q

Hyper IgM Syndromes Functional Defect

2 Listed

A
  • Failure of IgM class switching and somatic mutation
  • Lack of memory B cells
71
Q

Hyper IgM Syndromes: Consequence

4 Listed

A
  • Recurrent pyogenic infections
  • neutropenia
  • elevate IgM with absent IgG, IgA, IgE
  • decreased B cells
72
Q

Hyper IgM Syndromes Treatment

3 Listed

A
  • CD40 and CD40L defects are more difficult to treat (T cell defects require HCT)
  • AID defects treated with IVIG
  • Antibiotic prophylaxis
73
Q

Hyper IgM Syndrome 2 AKA

A

HIM2

74
Q

HIM2 AKA

A

Hyper IgM Syndrome 2

75
Q

Hyper IgM Syndrome 2 Inheritance pattern

A

Autosomal Recessive

76
Q

HIM2 mutation

A

Mutation in Activation Induced Deaminase (AID)

77
Q

HIM2 Mutation Consequence

A

Failure of IgM class switching and somatic mutation

78
Q

HIM2 Treatment

A

Because the defect is only B cells IVIG replacement and antibiotic prophylaxis is required

79
Q

HIM1 Inheritance Pattern

A

X-linked Recessive

80
Q

HIM13 Inheritance Pattern

A

Autosomal Recessive

81
Q

HIM1 Mutation

A

CD40L

82
Q

HIM3 Mutation

A

CD40

83
Q

Pathology of HIM1 & HIM3

5 Listed

A
  • Weak B/T cell interactions
  • defective somatic mutation
  • Defective class switching
  • Defective T cell/macrophage interactions
  • Lack of cell-mediated immunity
84
Q

Chronic Granulomatous Disease caused by?

A

Mutations in phagocyte NADPH oxidase (a component of the phagocyte oxidase)

85
Q

Chronic Granulomatous Disease Inheritance Pattern

A

X-Linked Recessive

86
Q

Chronic Granulomatous Disease functional defect and Consequence

2 Listed

A
  • inability of phagocytes to destroy certain microbes (primarily fungal and bacterial pathogens)
  • Leads to chronic T cell stimulation of macrophages and granuloma infection
87
Q

Chronic Granulomatous Disease Treatment

3 Listed

A
  • Lifelong antibacterial and antifungal prophylaxis
  • early diagnosis of infection
  • aggressive management of infection complications
88
Q

Chronic Granulomatous Disease Prognosis

A

average patient survives to 40 years old

89
Q

Chediak-Higashi Syndrome Caused by?

A

Mutations in CHS1/LYST protein (a protein involved in regulating and trafficking of lysosomes in the cell)

90
Q

CHS1/LYST protein function and disease involvement

2 Listed

A
  • a protein involved in regulating and trafficking of lysosomes in the cell
  • Involved in Chediak-Higashi Syndrome
91
Q

Chediak-Higashi Syndrome Functional Defect and Consequence

2 Listed

A
  • Defective lysosomal function in neutrophils, macrophages and dendritic cells, and defective granule function in natural killer cells
  • Causes Recurrent bacterial infections
92
Q

Other clinical aspects of Chediak-Higashi Syndrome

3 Listed

A
  • oculocutaneous albinism
  • coagulation defects
  • progressive neurological deterioration
93
Q

Chediak-Higashi Syndrome Treatment

2 listed

A
  • Hematopoietic stem cell transplant (this does not alter neurological aspects of disease)
  • Prophylactic antibiotics
94
Q

Chediak-Higashi Syndrome Prognosis

2 Listed

A
  • Without the transplant, death from bacterial infections before 7 years of age
  • Severe and debilitating neurological deficits by 20 years of age
95
Q

LAD AKA

A

Leukocyte Adhesion Deficiencies

96
Q

Leukocyte Adhesion Deficiencies AKA

A

LAD

97
Q

Leukocyte Adhesion Deficiencies Inheritance Pattern

A

Autosomal Recessive

98
Q

Leukocyte Adhesion Deficiencies Causes

A

failure of neutrophil recruitment to the site of infection

99
Q

LAD-1 Pathology

2 Listed

A
  • Failure of neutrophil recruitment to site of infection
  • also deficient T cell/APC interactions
100
Q

LAD-1 Deficiency

A
  • ß2 integrins (CD18, LFA-1, Mac-1) deficiency
101
Q

LAD-2 Deficiency

A

E and P-selectin ligands (CD62) deficiency

102
Q

LAD-3 Deficiency

A

Kindlin-3 deficiency results in decreased integrin activation

103
Q

Complement Deficiencies predispose patients to…

2 Listed

A
  • to bacterial infections (especially Neisseria species)

And/Or

  • Systemic Lupus Erythematosus
104
Q

Complement Deficiencies: Patients lose the activity of…

A

The defective protein but also the functions of the proteins that follow the particular cascade

105
Q

Complement Deficiencies Deficiencies can be in?

A

Specific complement components or in the complement regulatory proteins

106
Q

Complement Deficiencies Inheritance Pattern

A

Most are Autosomal Recessive

107
Q

Complement Deficiencies: Homozygous deficiency

A

most will have complete deficiency of the complement component

108
Q

Complement Deficiencies: Heterozygous deficiency

A
  • Are generally asymptomatic
  • 50% normal complement activity
109
Q

Complement Deficiencies Treatment

2 listed

A
  • vigilance for early signs of serious infection, vaccination
  • possible antibiotic prophylaxis
110
Q

Wiskott-Aldrich Syndrome Caused by?

A

mutations in X-chromosome protein Wiskott-Aldrich Syndrome Protein (WASp) protein expressed exclusively in hematopoietic cells and is involved in actin cytoskeleton remodeling

111
Q

Wiskott-Aldrich Syndrome Functional defect and Consequence

3 Listed

A
  • defective signaling from the cell membrane to the cytoskeleton
  • impaired cell signaling in T and B cells
  • Defective polarization, motility, and phagocytosis in neutrophils in neutrophils and macrophages
112
Q

Wiskott-Aldrich Syndrome Other Clinical Aspects

7 Listed

A
  • Variable presentation based on specific mutation
  • Thrombocytopenia
  • bleeding (petechiae or prolonged bleeding from umbilical stump of circumcision)
  • sever infections
  • eczema or varying severity
  • autoimmune manifestations
  • malignancies (lymphoma and leukemia)
113
Q

Wiskott-Aldrich Syndrome Treatment

4 Listed

A
  • prophylactic antibodies
  • platelet transfusions
  • IVIG in patients with antibody deficiency
  • Hematopoietic transplant
114
Q

Wiskott-Aldrich Syndrome Prognosis

2 Listed

A
  • bleeding is the main cause of death
  • malignancies are often fatal
115
Q

Relative occurrence of primary immunodeficiency Diseases

A
116
Q

Key features that suggest primary immunodeficiency disease

3 Listed

A
  • Recurrent infections
  • Severe infections
  • infections with normally avirulent pathogens
117
Q
A
118
Q
A
119
Q
A

Common Variable Immunodeficiency

120
Q
A

Leukocyte Adhesion Deficiency

FMS (34 decks)

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