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Flashcards in Small Group Deck (59):

RAG deficiency

B and T deficient but normal NK


Adenosine deaminase deficiency

T,B & NK cells absent)


JAK-3 deficiency

T cells


These patients have defective terminal B-cell differentiation, absence of plasma cell formation and antibody production. Early Bcell development is quite normal and is reflected by normal (even increased numbers) of Bcells in peripheral blood (detected by phenotyping) but a marked reduction in terminal Bcells,
plasma cell and reduced numbers of germinal centers in lymphoid tissue

common variable immunodeficiency (CVI),

The picture
is one of “frustrated” B-cell responses and the defects usually reside in some sort of
defective cytokine signaling or cross talk between B and Th2 cells, which prevents the Bcells
from differentiating to a later stage. Theoretically, abnormal T regs could be
suppressing B cell terminal differentiation.


Early appearance of ‘T-Cell’ type infectious diseases such as disseminated fungus and protoza and the marked decrease in lymphoid cells in her blood and tissues like tonsils and spleen.

severe combined immunodeficiency (SCID).

This type of presentation suggests an early lineage defect in a stem cell line that leads to
impaired production of lymphocytes but not neutrophils, platelets and erythrocytes (there are very rare defects that do involve all lineages). The defect in lymphocyte development is
usually associated with a growth signal or activating signal. Found commonly in SCID are
fundamental interleukin receptor defects that cause very broad defects in immune responses.

adenosine deaminase deficiency-retroviral mediated transfer of the adenosine deaminase
defective gene into the bone marrow stem cells of this type of patient can be curative.


Defect in early B-cell development that prevents differentiation and
proliferation of antibody forming cells.

The defect has been localized to the X chromosome and leads to defective tyrosine kinase signaling and subsequent defective or absence of appropriate display of B cell growth and survival receptors in many cases.

How to make a clinical diagnosis? What tests?

X-linked agammaglobulinemia

Inability to produce specific antibodies to the capsular antigens of pathogenic bacteria leads to suboptimal binding to C3b and Fcγ receptors on neutrophils, which, in turn, subsequently causes inefficient phagocytosis and bacterial killing. Persistent bacterial survival leads to clinical infection.

clinical diagnosis can be made simply by doing a serum protein electrophoresis and
absolute quantitation of the deficiency can be done techniques for each Ig isotype.


How can you detect IC in tissue? Describe the lab test.

The inflammatory reaction could be characterized by the use of fluorescinated or peroxidase
labeled anti IgG and anti C3 reagents that will detect immune complexes in tissue


What cytokines may induce muscle aches and
severe fatigue?

IL1 and IL6


once circulating autoimmune complexes of DNA and anti-
DNA are formed, what happens next?

complement and Fc receptor pathways are activated and serve as
generators of inflammation by a final common pathway (neutrophil recruitment).

Neutrophils & Monocyte phagocytosis via FcR or C3b
(also neutrophil recruited by C3a and C5a)


how indirect immunofluorescence of the area you decide to biopsy could explain the pathogenesis of his disease and how direct immunofluorescence could explain the actual etiologic agent of his disease

-indirect immunofluorescence tells you what response was. (IgG response or complement involved)
-direct tells you for specific pathogen…


What might the failure of a control serum with known anti-glomerular antibodies to stain the glomeruli of some patients indicate?

defect in collagen.

Goodpastures (antibody against type IV collagen)


How are the immunodominant peptides of these allergens are usually preferentially presented?

The immunodominant peptides of these allergens are usually preferentially presented in selected (Class II) D MHC loci by dendritic cells.


A common component of many of the environmental antigens is that they contain...

chitin-polysaccharide not found in mammals.


Late phase allergy reaction dep. totally on T cell activation and presence of which cytokines?

IL3, 4, 5, 13, TNF-α, GM-CSF and IL-10.


What does omalizumab and Ipilimumab treat?

omalizumab- (anti IGE antibodies)
Ipilimumab blocks CTLA-4


What are SCIT and SLIT?

Immunotherapy - given subcutaneous(allergy shots, SCIT) or sublingual(SLIT)

Sublingual Immunotherapy
Grastek - Timothy grass
Oralair - Kentucky blue, orchard, perennial rye, sweet vernal and timothy grass
Ragwitek - Ragweed


Life threatening infections soon after birth
Wasting, Failure to thrive
Lack of Thymic shadow

What cells missing (specifically)?

Severe Combined Immunodeficiency Disease (SCID)

Lack of CD3+, CD4+, CD8+ and lymphocyte response to antigens


What ligands are might someone w X-linked SCID be unable to respond to?

IL2, IL4, IL7, IL9, IL15

missing common gamma chain so failure to activate transcription of specific genes


Describe the RAST test, what is it used for?

Allergen in solid phase,
IgE (serum)

-patients serum added to a cellulose disc with covalently bound allergen

IgE binds to allergen (IgE present in serum binds to allergen)

After washing, radio-labeled anti-IgE added, radioactivity is countered w a gamma counter

In vitro assays should be considered only diagnostic adjuncts to an appropriate clinical setting.

Skin testing and RAST assays can be positive, but the patient may not have clinical symptoms.


Progesterone also stimulates the surface cells of the uterine
endometrium to display (BLANK) which in turn inhibits complement mediated cell death.

Progesterone also stimulates the surface cells of the uterine
endometrium to display decay accelerating factor (DAF or CD55-
see complement lecture) which in turn inhibits complement
mediated cell death


How can IBD be treated?
B. fragilis or B. subtilits?

IBD can be treated by Bacteroides fragilis which induces an anti-inflammatory response


What bacteria would protect against experimental EAE.

B frag. or B sub.

Intestinal bacteria can protect from experimental autoimmune encephalomyelitis (EAE)?


Explain why/how high fat diet induces changes in the microbiota that can promote obesity:

High fat diet affects innate lymphoid cells to secrete IL-22 which induces expression of anti-microbial peptides which will alter the microbiota.

high fat and carbohydrate diet leads to increase in Firmicutes and decrease in Bacteroidetes


Protection from WNV encephalitis is dependent upon the accumulation of which leukocytes?

Protection from WNV encephalitis is dependent upon the accumulation of CCR5+leukocytes including; CD4+, CD8+, CD14+ and CD56+.


Leprosy can incite either a Th1 (helper) or Th2 subset dominant response. Which form is the tuberculoid/lepromatoid?

How is each classified/characterized?

One, the tuberculoid form, is characterized by localized granulomas (clusters of macrophages, T cells, DC and necrotic debris). These patients are capable of mounting a normal Th1 response to the infection.

The other form, lepromatoid, is characterized by widespread infection, sparse cellular reactions in the organs involved and a poor prognosis. These patients are incapable of mounting a Th1 response to the organism

(malnutrition is associated with depressed Th function)


Why don’t all patients infected with M. leprae manifest similar clinical states?

How can one type be converted to the other?

genetic predisposition (B7 and CD28 co-receptors, if DC don't up regulate co receptors to T cells then cause anergy), some mount Th2 response vs Th1

The expression of the tuberculoid form of leprosy can be further influenced by any drug that inhibits T cell or macrophage activation. Thus cyclosporine (an immunosuppressant drug) or corticosteroids (potent antiinflammatory drug) can convert tuberculoid leprosy to the more lethal form


If you wanted to develop a vaccine against leprosy, what cytokines or other molecular structures (in theory) would be most logical to add to a living but attenuated leprosy preparation in order to mimic an actual infection?

The genes that would be considered in a vaccine would be Th1, including IL-12,
IFN-gamma; IL-21 and/or any other in the Th1 sequence that you think are critical to an
effective response. Molecular structures that act as PAMPs that produce Th1 TLR
activation via DC or Toll like receptors could also be possibilities.

-put in adjuvant for person’s vaccine… include some help w TLR. promoting cytokine to be more like Th1 … so add IL 12, IFNgamma, IL 18


Diphtheria is a bacterial infection that exerts many of its clinical effects by production of soluble protein exotoxins that circulate in the blood and damage the peripheral and cranial nervous system.

Here the pathogenic mediator is a soluble protein elaborated in extracellular fluid
by proliferating bacteria. The response needs to be rapid and one mediated by
antibodies that neutralize the toxin.
(antibodies want humoral (Th2) response)

In order to develop a vaccine, the antigen needs to be a toxoid type of protein that
mimics the real toxin and stimulates Th2 responses that will promote antibody
formation. Cytokines like IL-4 (could be combined with IL-6 and 10, and/or 21)
would be the most logical ones needed as an effective vaccine promoter and could
be linked to a toxoid type derivative of the toxin. Molecular copies of PAMPs that
are known to activate TLR that in turn activate Th2 responses could also be added
to the toxoid.


TB requires what type of response? Why might someone be extra susceptible to it?

How to test?

It is well known that this type of bacteria require a vigorous Th1 response for control.

defect in Th-1 cytokine production, defective Th-1 cytokine receptor synthesis or
loss of function mutations of Th1 activating TLR. The most likely defect is either
in IL-12, IL-18 or INF-γ.

One possibility
would be to probe mononuclear leucocytes isolated from these subjects with
antibodies to the receptors that could be involved. Since it appears that the
ultimate lethal defect in these patients is their inability to upregulate TNF-a
because of a deficiency in interferon-g, assays can be devised to measure whether
their mononuclear cells could indeed do so


Describe the principle of the tuberculosis skin test.

What type of hypersensitivity response?

What happens if a person has had TB in the past?

When will the test be negative?

The test exploits the fact that a DELAYED TYPE
HYPERSENSITIVITY response is necessary to resist tuberculous infection. If an individual currently has or had exposure to TB in the past and successfully
eradicated it or forced it to lie dormant in hilar lymph nodes, that individual should have immunologic memory of the encounter. The immune system can be ‘tricked” into thinking it is encountering the TB organism again by placing KILLED TB antigens under the skin. Memory Th cells will generate a
DELAYED TYPE HYPERSENSITIVITY response at the site of the deposited
antigen and this can be detected by the formation of a nodule caused by the recruitment of macrophages by IFN-g producing Th cells. If an individual has been previously infected but has a genetic defect that prevents DELAYED TYPE
HYPERSENSITIVITY, OR is on a drug that suppresses DELAYED TYPE HYPERSENSITIVITY, the skin test will be negative.


Describe the basic components of the Quantiferon Gold test.

The basic components of the assay are: patient mononuclear cells from the peripheral blood are incubated with very specific TB antigens. If the patient has immunity to TB, IFN-g will be released and can be
detected, even if present in minute amounts.


Why was there a broad spectrum of disease expression in both the model plane flyers and the drug abusers?

The variance in reactivity to antigens is due, in large part, to differences in how
they are presented by the varying MHC Class I and II determinants to immune
effector cells and /or the type of TLR that is activated on DC.


The patient had a parasitic infection transmitted by flies and endemic in central and western Africa. Predict what cytokine(s), if measured in her plasma, might be elevated in this patient’s blood.

What lab test to use?

IL-5, IL,4, IL-10, IL-13 (Th2 response)

Control of parasitic infections (e.g. Schistosoma mansoni) can be mediated by complement activation, but is also mediated by an IgE-dependent process known as antibody dependent cellular cytotoxicity (ADCC). During ADCC parasite specific IgE, bound to eosinophils via their Fc regions, recognize the invading parasite and induce eosinophil-dependent killing.

positive ELISA for parasite

when parasite, other things on that parasite your body responds to, so the secondary response is what is driving IgG


Two weeks after discharge, the patient, feeling extremely fortunate to be alive, bought a “lucky” bracelet at a State fair and avowed to “never take it off”. To her dismay, 3 weeks later she noted intense itching and a red, bumpy rash under the bracelet. What happened?

Here, the divalent nickel ion
leached out of the bracelet, diffused through her epidermis and combined with dermal
proteins. The nickel-protein complex was then taken up by DC and presented as an
antigen that induced Th1 cells that caused TMMI driven inflammation that manifested
itself as a rash.


The Ouchterlony or agar gel immunoprecipitin assay

The Ouchterlony or agar gel immunoprecipitin assay technique is a time revered immunologic assay that analyzes antigen-antibody precipitation in gels. Wells are punched into agar gel and antigens are placed in individual wells and antibodies-known or unknown- placed in opposing wells. The proteins are allowed to diffuse through the gel. If there is a specific antibody for the antigen diffusing towards it, a visible precipitation band will develop. The # of precipitin bands that form and their fusion patterns provide information on the number of specific antigens/antibody systems present and the isotype of the antibody


A patient had the misfortune of having severe asthma and Crohn’s disease. He had failed all forms of anti-inflammatory and immunosuppressive therapy. He was fed live whipworm ova harvested from pathogen free pigs every thirty days for 6 months. The patient went into a clinical remission of the inflammatory bowel disease. Amazingly, he also did not have another attack of asthma for over 2 years. A second patient had severe ulcerative colitis and infected himself with whipworms (relatively innocuous worm). The disease went into remission.

Predict what type of cell response is mediating inflammation in the gut in these 2 inflammatory bowel diseases. Also postulate what cytokines and T cell subsets might be found that usually aren’t found in the gut

In Crohn's, uncontrolled
Th1 driven inflammation led to destruction of the bowel mucosa and worse. [As
you might suspect, it has very recently been shown that many of the Th1 cells are
actually Th17 cells and the predominant cytokine is IL-23


Which cytokines promote OC diff? Which inhibit OC diff?

Proinflammatory cytokines IL1,IL6, IL8, TNFα and especially 17 induce RANKL and promote OC differentiation
Anti-inflammatory cytokines like IL4 & IL10 inhibit OC differentiation


What is Denosumab?

denosumab is an antibody… Denosumab is an human monoclonal antibody for treatment of osteoporosis.

is good at binding and soaking up the RANKL …by doing that you push balance back toward OB rather than OC.

Blocking RANKL with a monoclonal antibody (Denosumab) can lead to decreased bone loss


What is Pannus?

Pannus is inflammatory synovial tissue: source of cytokines that mediate bone loss.


How do macrophages regulate adipogenesis?

(in obesity?)

Macrophages regulate adipogenesis through WNT5a and TNF-like cytokines.
SFRP5: Secreted Frizzled-Related Protein 5; Frizzled is membrane receptor for WNT proteins. SFPR5 increases in obesity and metabolic syndrome.

White adipose tissue in Obese: increased macrophage infiltration


What is CCL2?

Cholesterol in the plaque attracts M1 pro-inflammatory macrophages
Macrophages secrete the chemokine CCL2 to attract monocytes and then prohibit them from exiting
Big plaque to ruptured plaque is clinical problem of huge dimensions


What cytokine may be be important cause of delirium, long term traumatic brain damage


Pro- inflammatory cytokines, especially IL-6, have potent effects on neural function and survival
May be important cause of delirium, long term traumatic brain damage

CD8, Th17 and activated glia cells produce IFNa, TNFα and IL17. These pro-inflammatory cytokines act on endothelial cells as well as astrocytes.
In these cells, NK-κB is activated and drives expression of IL6; consequently IL6 acts on endothelial cells and astrocytes in an autocrine pathway to amplify NF-κB response and IL6 production.
Neurons by secreting neurotransmitter stabilize this inflammatory response.


Devise proper type of response strategy-one must know the mechanisms causing the disease/syndrome

-Intracellular infections
-fungal infections
-toxins and organisms that resist phagocytosis

Cell Mediated Immunity for intracellular infections (live attenuated have better/stronger cell mediated response)

IL17 for fungal infections ( what could you do if Th17 cells were causing a disease?)

B cell response for toxins and organisms that resist phagocytosis

T & B responses for viruses

Generate memory cells in ALL cases


What type of vaccine is best for cell mediated response? (MHC?)

-- live attenuated the best for cell mediated (infect cells; MHC-I presentation)


Tumor antigens are usually self-proteins modified or selectively over expressed by a tumour
cell type specific (e.g)

So, if you use a antibody to target a specific cell type in a tumor, how would you target ...

B cell lymphoma
Prostate cancer

various tumors/melona
colon and recta
breast cancer

Tumor antigens are usually self-proteins modified or selectively over expressed by a tumour
cell type specific (e.g)

melanoma - MART-1, tyrosinase, Gp-100 (essentially melanocyte specific)

B cell lymphoma - CD20 (essentially B cell specific)

AML - CD33 (essentially myeloid specific)

Prostate cancer – PSA (prostrate specific antigen)

shared (e.g.)
MAGE-3 (various tumors, e.g. melanoma)

Carcinoembryonic antigen (CEA) (colon and rectal)

HER2/neu (over expressed in breast cancer)

Viral antigens: Human Papilloma Virus (HPV)


Explain mechanistically how tumor cells can reduce MHC I on their cell surface.

tumor cells have ability to reduce amount of MHC class I on cell surface. tumor cells will mutate TAP I and II so peptides don't get into ER, if they don't get into ER class I MHC molecules cannot traffic to cell surface bc they require peptides in the context of self for MHC class I to get to surface - down regulation of MHC class I can lead to protection from CD8 positive T cells.


What is Rituximab?

What is Trasturzumab?

monoclonal antibody against CD20?

CD20- Non-Hodgkins lymphoma

Trastuzumab- anti-HER2 antibody (TIL?) or Herceptin


What type of treatment is TIL?

One excellent example of cellular adoptive therapy of tumors is passive transfer
of tumor infiltrating lymphocytes (TILs).

effector T cells to treat cancer patinets

take tumor, isolate TIL… cell populations that have gone to site and must be reactive to tumor in some fashion, expand TIL and transport those back to individual

or take TIL and incubate w tumor fragments to increase their reactivity against particular tumor and infuse back in some patient…

-provides an exogenous source of anti-tumour T cells

Patient’s own T cells are activated in vitro and retransferred

-tumour specificity generated by:

-using defined tumour-specific antigen
-tumour infiltrating lymphocytes

-most effective for highly immunogenic tumours
-may be boosted by concurrent immunization with tumor associated antigen

-lack of persistence of transferred cells
-diverse specificities required


What does Ipilimumab do? Nivolumab?

Ipilimumab blocks CTLA-4
Nivolumab blocks PD-1


Relapsed acute B cell lymphoblastic leukemia has an extremely poor prognosis. Scientist/clinicians, using advanced molecular techniques, constructed a T cell receptor that recognized CD19 and also added a co-stimulatory gene and a T cell activating gene. This construct was combined with a viral vector and inserted in the patient’s T cell in vitro, now designated chimeric antigen receptor T cells, and then re-infused them into the patient. Several amazing things happened:

The patients went into remission.
The remissions were prolonged and possibly permanent.
Some patients developed a severe syndrome characterized by fever and shock.
The syndrome developed at varying times after infusion of the chimeric cells.
Most patients developed hypogammaglobulinemia


How are polymyositis and MG similiar and different?

Patients with polymyositis, another autoimmune disease that cause symptoms similar to myasthenia, have a completely different etiology of their disease. Their T cells are attacking muscle fibers and pay no attention to the neuromuscular junction. Muscle biopsies in these patients are completely different than those in myasthenia because they have a cellular mediated autoimmune disease.


How might the football player w MG be treated?

Once antibody was proven to be mediator of the disease, clinicians realized that mechanical removal of IgG (plasmapheresis) might at lease ameliorate symptoms and prevent patients from requiring ventilatory support.


What might high titers of anti-citrulline antibodies in their serum indicate?



How can smoking cause RA?

The provoking agent is tobacco smoke. Smoking is a common cause on inflammation of the bronchi. A toxic end product of tobacco smoke activates a gene(s) (likely by epigenetic methylation) in patients with a certain MHC-II complex that in turn converts arginine to citrulline. Heavily citrullinated peptides are then found in the bronchial inflammatory exudates and they are strongly antigenic. DC present them to Th2 B cells and the end result is the production of anti-citrullinated peptide antibodies. These antibodies combine with the citrullinated peptides in the bronchi initially and can be detected there long before a patient develops actual RA. If the patient continues to smoke, eventually the antibody response can be detected in peripheral blood and then in synovial fluid as immune complexes, phagocytized by joint macrophages that in turn release pro-inflammatory cytokines that can destroy cartilage.


How can a clinician intervene in patient w RA?

A clinician can intervene at many steps in the process. First-get the patient to stop smoking. Then use corticosteroids to block cytokine production, monoclonal antibodies that eliminate B cell or monoclonals that block IL-6 or TNF-a


What genetic deficiency?

immunodysregulation, polyendocrinopathy, enteropathy and the transmission is X-linked (IPEX syndrome).

FoxP3 mutations


What genetic deficiency?

polyendocrinopathy, candidiasis (a fungal infection), and ectodermal dysplasia (APECED syndrome)
low calcium in their blood, are infertile, have deep voices and abnormal skin and bone formation.

AIRE defects

In the AIRE defect, you can predict that there has been partial or complete loss of intra-thymic display of endocrine (and probably neuroendocrine) antigens which then allows you to expect and look for any number of endocrine deficiencies in these patients. Hypoparathyroidism (low calcium), hypothyroidism (deep voice) and ovarian/testicular dysfunction (infertility) are to be expected. The skin and bone abnormalities are likely due to loss of T cell control of bone and skin homeostasis.

The frequent fungal defects would make one think some form of Th1 helper defect might also be present or that the ectodermal dysfunction is somehow thwarting innate immunity structural defenses in a way that the immune system can’t fix.


Complete loss of these genes is a fatal defect but partial loss isn’t



What genetic deficiency?

markedly increased size of their lymph nodes and spleen and produce huge amounts of IgG antibodies.

markedly increased size of their lymph nodes and spleen and produce huge amounts of IgG antibodies.

defect in Fas mediated apoptosis

he marked increase in CD3+, CD4- & CD8- cells confirms the evidence that antigen stimulated cells lacking a co-stimulatory signal are expected to undergo apoptosis. These patients can’t do that and antigen bound T cells that have down- regulated their 4 or 8 surface markers but are unable to kill themselves “pile up” in lymphoid tissue and spleen

Their B cells appear to be poorly regulated and inappropriate numbers of B cells mature to plasma cells and produce a wide range of IgG antibodies that are reflected by the presence of polyclonal hypergammaglobulinemia. These patients may provide a window for further understanding B cell control.