Infectious Disease - Immunology - Immunodeficiencies; Immunomodulation; Transplants Flashcards
Which is much more common, primary or secondary immunodeficiencies?
Secondary
(due to malnutrition, drugs, infection, etc.)
Name a few causes of secondary immunodeficiency.
Which is most common?
Malnutrition (most common);
drugs;
infection;
etc.
An innate immune response against self is known as what?
An adaptive immune response against self is known as what?
Autoinflammation;
autoimmunity
What disorders are characterized by failed immune responses?
Immunodeficiencies
What are the top three warning signs for primary immunodeficiency in a neonate / child?
- ____________
- Need for _______ antibiotics
- _______ to _______
- Family history
- Need for IV antibiotics
- Failure to thrive
____% of identified cases of primary immunodeficiency before puberty are in males.
83% of identified cases of primary immunodeficiency before puberty are in males (often X-linked).
What general type of deficiency makes up the majority of cases of primary immunodeficiency?
Antibody deficiency / dysfunction
(~60% of cases)
Is the following information true regarding secondary immunodeficiencies?
Antibody deficiency / dysfunction = 60% of cases
Combined B cell and T cell defects = 20% of cases
T cell defects = 10% of cases
Phagocytic defects = 10% of cases
Complement defects = 2% of cases
No, the following is true regarding primary immunodeficiencies.
Antibody deficiency / dysfunction = 60% of cases
Combined B cell and T cell defects = 20% of cases
T cell defects = 10% of cases
Phagocytic defects = 10% of cases
Complement defects = 2% of cases
Recurrent bacterial infections (especially encapsulated) are typically indicative of dysfunction of ______ cells, ___________, and/or phagocytes.
Recurrent pyogenic bacterial infections (especially encapsulated) are typically indicative of dysfunction of B cells, complement, and/or phagocytes.
Recurrent viral infections are typically indicative of dysfunction of ______ cells or ______ cells.
Recurrent viral infections are typically indicative of dysfunction of T cells or B cells.
Recurrent fungal infections are typically indicative of dysfunction of ______ cells or ______ cells.
Recurrent fungal infections are typically indicative of dysfunction of T cells or phagocytic cells.
Most maternal IgG transfer across the placenta begins _________ before birth, and peaks at __________, and is gone at _________ after birth.
Most maternal IgG transfer across the placenta occurs 6 mo. before birth, and peaks at birth, and is gone at 6 mo. after birth.
Most maternal IgG transfer across the placenta occurs in which trimester?
The third
The low-point for infant antibody levels is _____ months when maternal antibodies have waned, and the child’s antibody production is still ramping up (although Ig__ is already present; Ig__ lags for the first few years).
The low-point for infant antibody levels is 6 months when maternal antibodies have waned, and the child’s antibody production is still ramping up (although IgM is already present; IgA lags for the first few years).
What is the most frequent primary immunodeficiency?
Selective IgA deficiency (~1/500)
Selective IgA deficiency is diagnosed by serum IgA below what level?
How does it manifest?
< 10 mg/dL.
Typically asymptomatic, but may be recurrent GI infections and increased risk for autoimmune and endocrine disorders
What is defective in Bruton’s X-linked agammaglobulinemia?
Bruton’s tyrosine kinase (BTK)
–>
no maturation from pre-B cells
–>
no antibodies produced
What B cell type is found in Bruton’s X-linked agammaglobulinemia?
Pre-B cells
(no progression to mature cells)
Which antibodies are decreased in Bruton’s X-linked agammaglobulinemia?
All of them
In Bruton’s X-linked agammaglobulinemia, infections begin at ___________ of life (mostly bacterial pneumonia or otitis media but may also be viral GI issues).
In Bruton’s X-linked agammaglobulinemia, infections begin at 4 - 6 months of life (mostly bacterial pneumonia or otitis media but may also be viral GI issues).
What might be some physical or laboratory signs of Bruton’s X-linked agammaglobulinemia?
How is it treated?
Abesent tonsils,
no B cells in serum;
IV Ig
What is the diagnosis?
What is another name for it?
Hyper-IgM syndrome;
CD40L deficiency
What inheritance pattern does hyper-IgM syndrome (CD40L deficiency) show?
X-linked
Besides impaired antibody class switching, hyper-IgM syndrome also leads to decreased ____________ secretion and ____________.
Besides impaired antibody class switching, hyper-IgM syndrome also leads to decreased chemokine secretion and phagocytosis.
Hyper-IgM syndrome is characterized by decreased _________ count and recurrent _________ infections.
Hyper-IgM syndrome is characterized by decreased neutrophil count and recurrent bacterial infections.
How is hyper-IgM syndrome treated?
Bone marrow transplant or IV Ig replacement
How common are complement deficiencies?
Very rare
Complement deficiencies are very rare.
- A deficiency of ______________ leads to hereditary angioedema.
- A deficiency of ______________ are associated with autoimmunity.
- A deficiency of ______________ leads to recurrent Neisseria spp. infection (especially recurrent meningitis from N. meningitidis).
Complement deficiencies are very rare.
- A deficiency of C1 inhibitor leads to hereditary angioedema.
- A deficiency of early complement (C1 - C4) are associated with autoimmunity.
- A deficiency of late complement (C5 - C9) leads to recurrent Neisseria spp. infection (especially recurrent meningitis from N. meningitidis).
Complement deficiencies are very rare.
- A deficiency of C1 inhibitor leads to ______________.
- A deficiency of early complement (C1 - C4) are associated with ____________.
- A deficiency of late complement (C5 - C9) leads to recurrent ____________ infection (especially recurrent meningitis from ____________).
Complement deficiencies are very rare.
- A deficiency of C1 inhibitor leads to hereditary angioedema.
- A deficiency of early complement (C1 - C4) are associated with autoimmunity.
- A deficiency of late complement (C5 - C9) leads to recurrent Neisseria spp. infection (especially recurrent meningitis from N. meningitidis).
________ _______ deficiencies result in impaired ability for leukocytes to get to the site of infection due to defective leukocyte _________.
Leukocyte adhesion deficiencies result in impaired ability for leukocytes to get to the site of infection due to defective leukocyte integrins.
Leukocyte adhesion deficiencies are characterized by the following:
Recurrent _______ _______ (tissue type) infection.
Delayed _______ _______ separation.
Severe _____________ (body location) disease.
No ________ formation despite high WBC counts.
Leukocyte adhesion deficiencies are characterized by the following:
Recurrent soft tissue infection.
Delayed umbilical cord separation.
Severe periodontal disease.
No pus formation despite high WBC counts.
Which is the more common form of primary immunodeficiency, Chediak-Higashi or chronic granulomatous disease?
Chronic granulomatous disease
(Chediak-Higashi is very rare)
You find out that besides his staphylococcal infections, this boy has had Nocardia and Aspergillus cutaneous infections as well. Upon further examination, you notice he has granulomas of his liver, lungs, and lymph nodes.
What confirmatory test can you use to diagnose his underlying condition?
Nitroblue tetrazolium
OR
chemiluminescene test
(chronic granulomatous disease)
Why do patients with Chediak-Higashi syndrome often have partial albinism?
Melanin deficiency
(defects in granules)
What is the underlying cause of chronic granulomatous disease?
NADPH oxidase deficiency
What is the underlying cause of Chediak-Higashi syndrome?
Lack of lysosome + phagosome fusion
(i.e. poor phagolysosome formation)
T cell deficiencies can lead to an increased susceptibility to what infection types?
All types.
Intracellular infections
Viruses
Fungi
Protozoa
Mycobacteria
Extracellular infections
Other bacteria
What is the most common cause of SCID?
X-linked SCID due to gamma chain deficiency
(T cells no longer make interleukin receptors –> No T cells made –> B cells don’t function well without T cells)
What enzymes are the only available methods for ‘cleaning up’ purine metabolism waste products in leukocytes?
(Other cell types have more enzymes.)
Adenosine deaminase;
purine nucleotide phosphorylase
Why do adenosine deaminase deficiencies selectively damage B cells and T cells?
B cells and T cells have no back-up methods of purine metabolism waste cleanup
(most cells do)
What causes autosomal recessive SCID?
Issues in VDJ recombination (e.g. RAG defects)
What is the diagnosis?
SCID
True/False.
There are clearly defined methods of determining the specific molecular cause of SCID.
True.
Fill in the blanks for DiGeorge syndrome:
Variable __________ cells
Diagnosed by absence of _______ _______ on CXR
Hypocalcemia, congenital heart disease, thymic aplasia, characteristic facies (low, rotated ears + broad nasal bridge + abnormal ________), sometimes mental retardation
_____ gene (chromosome 22) involved in cell migration pouches 3 and 4
Treatment: ________ transplant
Fill in the blanks for DiGeorge syndrome:
Variable B and T cells
Diagnosed by absence of thymic shadow on CXR
Hypocalcemia, congenital heart disease, thymic aplasia, characteristic facies (low, rotated ears + broad nasal bridge + abnormal philtrum), sometimes mental retardation
TBX gene (chromosome 22) involved in cell migration pouches 3 and 4
Treatment: Thymic transplant
Wiskott-Aldrich syndrome is characterized by actin defects in _________ and _________.
Wiskott-Aldrich syndrome is characterized by actin defects in leukocytes and platelets.
What mnemonic is useful for remembering the features of Wiskott-Aldrich syndrome?
WATER
Wiskott
Aldrich
Thrombocytopenia
Eczema
Recurrent infection
(also, elevated IgA and IgE)
What infection type is increased by a deficiency of any of the following?
IFN-Gamma receptor
IL-2 receptor
IL-12 receptor deficiencies
Mycobacterial infection
When is proper T cell function assessed during perinatal / childhood development?
Newborn screening: Bloodspot (Guthrie) card
(T cell receptor excision circles — excised DNA from recombination during T cell development)
What might be indicated by infections that are either too too severe, too invasive, too frequent, too protracted, or caused by unusual organisms?
Immunodeficiency
What is the molecular cause of all common variable immunodeficiencies?
Many, many genetic causes
When does common variable immunodeficiency (late-onset hypogammaglobulinemia) present?
How common is it?
2nd or 3rd generation of life;
fairly common (~1/5000)
What immunodeficiency is represented here?
Common variable immunodeficiency
Name a few causes of secondary immunodeficiency.
How can you check a patient’s ability to produce antibodies / mount an immune response?
Check their response to their past vaccinations
What two tests can be used to determine the number / type of WBCs in the blood?
CBC;
flow cytometry
How can an antibody deficiency be treated?
How can a complement deficiency be treated?
IV Ig;
plasma transfusion
Why did we stop using the live polio vaccine in the U.S.?
It caused actual polio in immunocompromised children
How do vaccines prevent infection?
They don’t;
they just increase the speed with which the body responds
True/False.
While vaccines save millions of lives, it is worth noting that most cases of vaccine-preventable diseases do not cause severe disease.
True.
E.g. most polio infections do not result in paralysis, most measles cases do not result in encephalitis, etc.
Acute inflammation leads to tissue _______.
Chronic inflammation leads to tissue _______.
Acute inflammation leads to tissue repair.
Chronic inflammation leads to tissue damage.
What antibody suffix characterizes murine (mouse) antibodies?
-Momab
(mouse)
What antibody suffix characterizes chimeric antibodies?
-Ximab
(chimeric)
What antibody suffix characterizes humanized monoclonal antibodies?
-Zumab
(humanized)
What antibody suffix characterizes fully human monoclonal antibodies?
-Mumab
(muman = human)
_________ _________ can be used in many diseases to disrupt many aspects of the immune system (bind IgE and their receptors, leukotrienes and their receptors; bind TNF and its receptors; bind IL-2, IL17, and other ILs; etc.).
Monoclonal antibodies can be used in many diseases to disrupt many aspects of the immune system (bind IgE and their receptors, leukotrienes and their receptors; bind TNF and its receptors; bind IL-2, IL17, and other ILs; etc.)
What is CAR T cell therapy?
Chimeric antigen receptor T cell modification –> cancer treatment
What process can be used to take antibodies or other non-chelatable substances out of the blood?
Plasmapheresis
Specific _________ can be given after toxin exposure (e.g. tetanus or botulinum) to provide passive immunity.
Specific immunoglobulins can be given after toxin exposure (e.g. tetanus or botulinum) to provide passive immunity.
What proportion of transplants are in women?
And in men?
1/3
2/3
The MHC (HLA) region is on what chromosome?
Chromosome 6
There are ___ total MHC alleles per person (these are what are compared for transplant matching).
___ MHC class I (2 HLA-A, 2 HLA-B, 2 HLA-C)
___ MHC class II (2 HLA-DP, 2 HLA-DQ, 2 HLA-DR)
There are 12 total MHC alleles per person (these are what are compared for transplant matching).
6 MHC class I (2 HLA-A, 2 HLA-B, 2 HLA-C)
6 MHC class II (2 HLA-DP, 2 HLA-DQ, 2 HLA-DR)
Which MHC class is made of an α-heterodimer and a β-heterodimer?
Which MHC class is made of an α-homotrimer and a β2-microglobulin?
MHC class II
MHC class I
In transplants, T cells bind foreign _____ which triggers an immune response.
In transplants, T cells bind foreign MHCs which triggers an immune response (positive selection ensured that T cells ‘know’ the difference between self and foreign MHC).
What is the main APC that is present in nearly every tissue?
Dendritic cells
A graft to one’s own self is called what?
An autograft (autogeneic)
A graft from one monozygotic twin to the other is called what?
An isograft (syngeneic)
A graft from one member of a species to another is called what?
An allograft (allogeneic)
A graft from one species to the other is called what?
A xenograft (xenogeneic)
The degree of transplant rejection is correlated with what?
MHC polymorphisms and genetic disparity
A patient has received a small skin graft from a donor who also donated this patient a graft several months ago.
Two days later you inspect the graft and notice that it is bright white. What type of hypersensitivity reaction is this?
This is an example of ___________-set rejection.
Type III hypersensitivity reaction (antigen-antibody complexes block up / prevent angiogenesis and vascularization of graft)
This is an example of second-set rejection.
A patient has received a small skin graft from a donor who also donated this patient a graft several months ago.
Twelve days later, you inspect the graft and notice that it is necrotic.
This is an example of ___________-set rejection.
What type of cell mediates this process?
This is an example of primary-set rejection.
TC cells
Describe the following host v. graft outcomes for a small graft without vascular anastomoses:
___________-set rejection — destruction of graft after 10–20 days by _______ cells due to immunological memory (MUST BE A SECOND GRAFT).
___________-set rejection — no vascularization of graft after ______ days due to immunological memory (MUST BE A SECOND GRAFT). This is a type III hypersensitivity reaction that prevents ____________ by occluding the new vessels.
Describe the following host v. graft outcomes for a small graft without vascular anastomoses:
Primary-set rejection — destruction of graft after 10–20 days by TC cells due to immunological memory (MUST BE A SECOND GRAFT).
Secondary-set rejection — no vascularization of graft after 2 days due to immunological memory (MUST BE A SECOND GRAFT). This is a type III hypersensitivity reaction that prevents angiogenesis by occluding the new vessels.
Soon after a liver is grafted into a patient, it rapidly turns white over the course of the next hour.
What has occurred?
Hyperacute rejection
(preformed antibodies against organ endothelium)
Describe the various types of transplant rejection.
What mediates hyperacute transplant rejection?
Preformed antibodies
What mediates acute transplant rejection?
CD8+ T cells
(Type IV)
What transplant rejection is characterized by interstitial fibrosis and vascular narrowing?
Chronic
What are some common mechanisms of action by which immunosuppressive medications given for transplants work?
IL-2 downregulation
After bone marrow is taken, how is it grafted into the recipient?
Via IV
(grafted bone marrow cells home back to the bone medulla)
True/False.
Graft v. host disease occurs commonly with bone marrow and liver transplants.
True.
It goes away eventually –> death of grafted leukocytes and growth of new self leukocytes from grafted bone marrow.
How does graft v. host disease resolve?
The death of grafted leukocytes
+
growth of new self leukocytes from grafted bone marrow
What cell types mediate graft v. host disease?
Donor TH and TC cells
The severity of graft v. host disease depends on the size of the _______ disparity.
The severity of graft v. host disease depends on the size of the MHC disparity.
True/False.
Cross-presentation plays a major role in graft v. host disease.
True.
Cross-presentation plays a role in graft v. host disease — In this process, ___________ antigens are displayed on APC MHC I to activate TC cells.
Cross-presentation plays a role in graft v. host disease — In this process, exogenous antigens are displayed on APC MHC I to activate TC cells (usually, MHC I displays endogenously synthesized antigens).
_________ _____recognition is the process by which donor-derived major histocompatibility complex (MHC)-peptide complexes (typically presented by donor-derived ‘passenger’ dendritic cells) are recognised directly by recipient T cells.
Direct allorecognition is the process by which donor-derived major histocompatibility complex (MHC)-peptide complexes (typically presented by donor-derived ‘passenger’ dendritic cells) are recognised directly by recipient T cells.
In ________ ____recognition, the alloantigens derived from graft are internalized, processed and presented in form of peptides by recipient’s APCs on their MHC II molecules.
In indirect allorecognition, the alloantigens derived from graft are internalized, processed and presented in form of peptides by recipient’s APCs on their MHC II molecules.
Direct allorecognition involves recognition of alloantigens by what?
Indirect allorecognition involves recognition of alloantigens by what?
Recipient T cells;
recipient APCs
