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
2
Q
Primary Immunodeficiency Disease Primary (Congenital)
A
- Mutation/defect is present at birth perinatally
- Not caused by damage to the immune system (secondary)
3
Q
Primary Immunodeficiency
A
Mutation/defect is present at birth
4
Q
Secondary immunodeficiency
A
Not caused by damage to the Immune system
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
6
Q
Primary Immunodeficiency Disease is almost always a genetic defect because?
A
7
Q
How many Primary Immunodeficiency Diseases are there?
A
>200 distinct Primary Immunodeficiency Diseases
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)
9
Q
Primary Immunodeficiency Diseases are associated with unexpected pathology such as
3 Listed
A
- Autoimmune diseases
- Cancer
- Allergy
10
Q
Primary Immunodeficiency Diseases: Defects of innate immunity
4 Listed
A
11
Q
Primary Immunodeficiency Diseases: Defects of lymphocyte Maturation
5 Listed
A
12
Q
Primary Immunodeficiency Diseases: Defects of lymphocyte Activation
4 Listed
A
13
Q
Primary Immunodeficiency Diseases: Other genetic disease with lymphocyte abnormalities
A
14
Q
Inheritance of Primary Immunodeficiency Diseases
2 Distinct Patterns
A
- Autosomal Recessive Inheritance (requires 2 defective genes)
- X-linked Recessive
15
Q
Primary Immunodeficiency Diseases: Autosomal Recessive Inheritance Pattern
2 Listed
A
16
Q
Primary Immunodeficiency Diseases: X-Linked Recessive Inheritance Pattern
4 Listed
A
17
Q
Defects in Lymphocyte Maturation Disease Examples
5 Listed
A
18
Q
Combines Immunodeficiency Syndromes occur in 1/? live births
A
1/58,000 live births
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
20
Q
Disorders arising from disturbances in the development of B and T cells may also involve?
A
Natural Killer (NK) Cells
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
22
Q
Since 2010 90% of newborns in the U.S> are screened for?
A
SCID
23
Q
SCID Patient Presentations
5 Listed
A
- Severe infections
- Lymphopenia
- Chronic Diarrhea
- Adverse reactions to live vaccines
- recurrent fevers
24
Q
Treatment of Combined Immunodeficiency Syndromes
A
Hematopoietic cell transplantation (HCT)
25
Combined Immunodeficiency Syndromes Prognosis
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
26
T Cell Receptor Excision Circles are?
27
TRECs Properties
4 Listed
28
Patients with SCID will not have mature T cells so they will not have \_\_\_\_\_\_\_\_\_
TRECs in the blood
29
X-Linked Severe Combined Immunodeficiency Disease: what type of mutation is most common?
99% of X-linked SCID are caused by γc Mutations
30
X-linked SCID prognosis
Fatal in the first year or 2 of life if not treated
31
X-linked SCID are symptomatic/asymptomatic at birth
Asymptomatic at birth and time of testing
32
X-linked SCID: undiagnosed patients present in the first year with?
5 Listed
* Recurrent opportunistic infections
* Chronic diarrhea
* Thrush
* Otitis media
* Failure to thrive
33
γc deficiency =
X-linked Severe Combined Immunodeficiency
34
γc is shared among many?
Cytokine receptors
* IL-2
* IL-4
* IL-7
* IL-9
* IL-15
* IL-21
35
IL-7 is required for?
T cell development and differentiation
36
IL-7 is produced in the ________ and signals through the _________ receptor to induce \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
* Thymus
* IL7R/γc
* proliferation of pro-T cells
37
With γc deficiency, the effect on B cells is?
* B cell number will be normal but serum Ig will be low because there are no CD4+ T cells to stimulate B cells
38
Autosomal Severe Combined Immunodeficiency: mutations in nucleotide salvage pathway Percentages
* ~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
39
ADA and PNP are both involved in?
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
40
Deficiency in ADA or PNP causes?
Build up of toxic deoxyadenosine
41
Treatment for ADA or PNP SCID
2 Listed
* Hematopoietic Cell Transplant
* Enzyme replacement therapy (weekly intramuscular injection)
42
ADA AKA
Adenosine Deaminase Enzyme (ADA)
43
PNP AKA
Purine Nucleotide Phosphorylase (PNP)
44
ADA and PNP deficiency toxic buildup of deoxyadenosine causes
2 Listed
* Decreased DNA synthesis
* Decreased Lymphocytes
45
RAG1 and RAG2 are?
proteins that are involved in VDJ recombination
46
Without RAG1 and RAG2 functionality
3 Listed
* 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
47
For Survival Pre-B cells require:
4 Listed
* Successfully rearranged H chain
* Association with surrogate light chains
* Association with Ig-signaling molecules
* Basal signaling
48
Btk Deficiency: X-linked agammaglobulinemia
can't get mature B cells
49
DiGeorge Syndrome caused by
2 Listed
* deletion in chromosome 22q11.2
* resulting in abnormal embryonic development of the pharyngeal pouch system
50
Functional Defect in DiGeorge Syndrome
Rudimentary or absent thymus
51
The consequence of DiGeorge Syndrome
2 Listed
* Decreased T cells
* Normal B cells but normal or reduced serum Ig (SCID)
52
Clinical Aspects of DiGeorge
5 Listed
* Rudimentary or absent thymus
* Cardiac Anomalies
* Hypocalcemia (from parathyroid hypoplasia)
* Palatal defects
* Gastrointestinal defects
53
Treatment of DiGeorge Syndrome
* Hematopoietic Cell Transplant (does not fully restore T cell repertoire but does provide adequate immune function)
54
Prognosis of DiGeorge Syndrome
Median survival with transplant is 5 years (oldest survivors are in their 20s)
55
Examples of defects of lymphocyte activation
5 Listed
* 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
Common Variable Immunodeficiency is not a?
Not a single disease
57
Common Variable Immunodeficiency Prevalance
1/25,000
58
Common Variable Immunodeficiency is a Collection of?
Collection of hypogammaglobulinemia syndromes
59
hypogammaglobulinemia syndromes are resulting from
many genetic defects
60
Common Variable Immunodeficiency: Variable because?
5 Listed
Variable - heterogeneous clinical manifestations
* Recurrent Infections
* Chronic Lung Disease
* Autoimmune Disorders
* Gastrointestinal Disease
* Susceptibility to lymphomas
61
Common Variable Immunodeficiency Age of diagnosis
2 Listed
* 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
Common Variable Immunodeficiency: Specific Gene Defect
2 Listed
* the specific molecular defect is known only for a small subset of patients
* likely results from a number of different gene defects
63
Common Variable Immunodeficiency: Consequence
impaired B cell differentiation with hypogammaglobulinemia
64
Common Variable Immunodeficiency: Treatment
IVIG to replace low serum Ig
65
Hyper IgM Syndromes prevalence
Rare: 1 / 1,000,000
66
Hyper IgM Syndromes different mutations Examples
3 Listed
* Activation-induced deaminase (AID)
* CD40L
* CD40
67
AID Inheritance Pattern
Autosomal Recessive
68
CD40L Inheritance Pattern
X-Linked Recessive
69
CD40 Inheritance Pattern
Autosomal Recessive
70
Hyper IgM Syndromes Functional Defect
2 Listed
* Failure of IgM class switching and somatic mutation
* Lack of memory B cells
71
Hyper IgM Syndromes: Consequence
4 Listed
* Recurrent pyogenic infections
* neutropenia
* elevate IgM with absent IgG, IgA, IgE
* decreased B cells
72
Hyper IgM Syndromes Treatment
3 Listed
* CD40 and CD40L defects are more difficult to treat (T cell defects require HCT)
* AID defects treated with IVIG
* Antibiotic prophylaxis
73
Hyper IgM Syndrome 2 AKA
HIM2
74
HIM2 AKA
Hyper IgM Syndrome 2
75
Hyper IgM Syndrome 2 Inheritance pattern
Autosomal Recessive
76
HIM2 mutation
Mutation in Activation Induced Deaminase (AID)
77
HIM2 Mutation Consequence
Failure of IgM class switching and somatic mutation
78
HIM2 Treatment
Because the defect is only B cells IVIG replacement and antibiotic prophylaxis is required
79
HIM1 Inheritance Pattern
X-linked Recessive
80
HIM13 Inheritance Pattern
Autosomal Recessive
81
HIM1 Mutation
CD40L
82
HIM3 Mutation
CD40
83
Pathology of HIM1 & HIM3
5 Listed
* Weak B/T cell interactions
* defective somatic mutation
* Defective class switching
* Defective T cell/macrophage interactions
* Lack of cell-mediated immunity
84
Chronic Granulomatous Disease caused by?
Mutations in phagocyte NADPH oxidase (a component of the phagocyte oxidase)
85
Chronic Granulomatous Disease Inheritance Pattern
X-Linked Recessive
86
Chronic Granulomatous Disease functional defect and Consequence
2 Listed
* inability of phagocytes to destroy certain microbes (primarily fungal and bacterial pathogens)
* Leads to chronic T cell stimulation of macrophages and granuloma infection
87
Chronic Granulomatous Disease Treatment
3 Listed
* Lifelong antibacterial and antifungal prophylaxis
* early diagnosis of infection
* aggressive management of infection complications
88
Chronic Granulomatous Disease Prognosis
average patient survives to 40 years old
89
Chediak-Higashi Syndrome Caused by?
Mutations in CHS1/LYST protein (a protein involved in regulating and trafficking of lysosomes in the cell)
90
CHS1/LYST protein function and disease involvement
2 Listed
* a protein involved in regulating and trafficking of lysosomes in the cell
* Involved in Chediak-Higashi Syndrome
91
Chediak-Higashi Syndrome Functional Defect and Consequence
2 Listed
* Defective lysosomal function in neutrophils, macrophages and dendritic cells, and defective granule function in natural killer cells
* Causes Recurrent bacterial infections
92
Other clinical aspects of Chediak-Higashi Syndrome
3 Listed
* oculocutaneous albinism
* coagulation defects
* progressive neurological deterioration
93
Chediak-Higashi Syndrome Treatment
2 listed
* Hematopoietic stem cell transplant (this does not alter neurological aspects of disease)
* Prophylactic antibiotics
94
Chediak-Higashi Syndrome Prognosis
2 Listed
* Without the transplant, death from bacterial infections before 7 years of age
* Severe and debilitating neurological deficits by 20 years of age
95
LAD AKA
Leukocyte Adhesion Deficiencies
96
Leukocyte Adhesion Deficiencies AKA
LAD
97
Leukocyte Adhesion Deficiencies Inheritance Pattern
Autosomal Recessive
98
Leukocyte Adhesion Deficiencies Causes
failure of neutrophil recruitment to the site of infection
99
LAD-1 Pathology
2 Listed
* Failure of neutrophil recruitment to site of infection
* also deficient T cell/APC interactions
100
LAD-1 Deficiency
* ß2 integrins (CD18, LFA-1, Mac-1) deficiency
101
LAD-2 Deficiency
E and P-selectin ligands (CD62) deficiency
102
LAD-3 Deficiency
Kindlin-3 deficiency results in decreased integrin activation
103
Complement Deficiencies predispose patients to...
2 Listed
* to bacterial infections (especially Neisseria species)
And/Or
* Systemic Lupus Erythematosus
104
Complement Deficiencies: Patients lose the activity of...
The defective protein but also the functions of the proteins that follow the particular cascade
105
Complement Deficiencies Deficiencies can be in?
Specific complement components or in the complement regulatory proteins
106
Complement Deficiencies Inheritance Pattern
Most are Autosomal Recessive
107
Complement Deficiencies: Homozygous deficiency
most will have complete deficiency of the complement component
108
Complement Deficiencies: Heterozygous deficiency
* Are generally asymptomatic
* 50% normal complement activity
109
Complement Deficiencies Treatment
2 listed
* vigilance for early signs of serious infection, vaccination
* possible antibiotic prophylaxis
110
Wiskott-Aldrich Syndrome Caused by?
mutations in X-chromosome protein Wiskott-Aldrich Syndrome Protein (WASp) protein expressed exclusively in hematopoietic cells and is involved in actin cytoskeleton remodeling
111
Wiskott-Aldrich Syndrome Functional defect and Consequence
3 Listed
* 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
Wiskott-Aldrich Syndrome Other Clinical Aspects
7 Listed
* 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
Wiskott-Aldrich Syndrome Treatment
4 Listed
* prophylactic antibodies
* platelet transfusions
* IVIG in patients with antibody deficiency
* Hematopoietic transplant
114
Wiskott-Aldrich Syndrome Prognosis
2 Listed
* bleeding is the main cause of death
* malignancies are often fatal
115
Relative occurrence of primary immunodeficiency Diseases
116
Key features that suggest primary immunodeficiency disease
3 Listed
* Recurrent infections
* Severe infections
* infections with normally avirulent pathogens
117
118
119
Common Variable Immunodeficiency
120
Leukocyte Adhesion Deficiency
