Tolerance, Autoimmunity, and Primary Immunodeficiencies

often affect women more than men, tend to be chronic, and may cluster with other conditions.

autoimmune diseases

3 multiple choice options

when the immune system can’t tell the difference between you and invaders, this breakdown is called a loss of self-_________________.

tolerance

3 multiple choice options

select all that apply:

what are the mechanisms of autoimmunity?

1. autoreactive T cells

2. autoantibodies

3. often both are involved

occurs early in lymphocyte development (in the thymus for T cells, bone marrow for B cells). self-reactive cells are deleted here. but... it's only 60-70% efficient! so some bad eggs still slip through.

central tolerance

3 multiple choice options

picks up the slack after cells exit primary lymphoid organs. happens in secondary lymphoid tissues (like lymph nodes, spleen).

peripheral tolerance

3 multiple choice options

shutting down a T/B cell's response

anergy

3 multiple choice options

select all that apply:

how does the immune system eliminate or train self-reactive lymphocytes early during development?

1. starts with lymphoid precursors → immature B and T cells

2. precursors enter the bone marrow or thymus

3. once in the primary lymphoid organ, they're exposed to self-antigens, and one of three things happens

4. they do NOT react to self-antigen → good to go

5. they react strongly to self-antigen → apoptosis

6. they become regulatory T cells

negative selection in the thymus. if the receptor binds too tightly to self-MHC + self-antigen, it's deleted.

T-cells

3 multiple choice options

mostly deleted if they bind to self-antigen in the bone marrow. however, some low-affinity binders may enter circulation and get dealt with in the spleen.

B-cells

3 multiple choice options

select all that apply:

if a mature lymphocyte encounters a self-antigen, what are three things can happen?

1. apoptosis: it's deleted

2. anergy: it becomes functionally inactivated

3. regulation: suppressed by Tregs

select all that apply:

what are the built-in ways T cells can be kept in check?

1. ignorance

2. anergy

3. exhaustion

T-cell never sees the antigen (maybe it's in an immune-privileged site like the brain or eye) OR there's not enough antigen to trigger a response.

it just minds its business.

ignorance

3 multiple choice options

T-cell sees the antigen but doesn't get a co-stimulatory signal (like CD28-B7). result: The T-cell is turned off in a tolerogenic way.

anergy

3 multiple choice options

T-cell is chronically stimulated (e.g., during ongoing infection or cancer). it becomes dysfunctional—this is super important in chronic viral infections and tumors.

exhaustion

3 multiple choice options

B-cell recognizes antigen (signal 1) and presents it to a helper T cell. T-cell expresses CD40L, which binds to CD40 on the B cell → signal 2. result = full activation →

antibody secretion

3 multiple choice options

B cell gets signal 1 (sees the antigen), but there's no CD40L from T cells, so: no signal 2 = no help. result: B cell becomes ___________________ (inactive, won't make antibodies)

anergic

3 multiple choice options

APC (like a dendritic cell) shows antigen on MHC II to a CD4+ T cell. two signals happen: TCR binds MHC+peptide (signal 1) and CD28 binds B7 on the APC (signal 2). result = full activation → _________________ → T cell proliferation and effector function.

IL-2 production

3 multiple choice options

if only signal 1 is given for the T-cell (e.g., antigen from a regular tissue cell without B7): no ____________. T cell becomes anergic → unresponsive, tolerized

co-stimulation

3 multiple choice options

CD4⁺ FoxP3⁺ CD25^hi

FoxP3 = master transcription factor for Treg function

CD25 = IL-2 receptor alpha chain (low-affinity) → important for sensing and scavenging IL-2

CD25 lets Tregs monitor when other T cells are nearby (producing IL-2), so they can swoop in and ______________________.

suppress immune responses

3 multiple choice options

select all that apply:

how do Tregs suppress other T-cells?

1. secrete anti-inflammatory cytokines

2. cytolysis (maybe)

3. soak up IL-2:

4. Block DC function

Tregs use __________________ to bind to CD80/86 on dendritic cells → blocks co-stimulation. prevents activation of new naïve T cells

CTLA-4

3 multiple choice options

Tregs release these, which are _____________: IL-10, TGF-β, IL-35 → suppress effector T cells

inhibitory cytokines

3 multiple choice options

Tregs can kill effector T cells via granzyme/perforin

cytosis

3 multiple choice options

Tregs express CD25 to soak up IL-2 → starving effector T cells. also disrupt energy metabolism with adenosine production

metabolic disruption

3 multiple choice options

a specialized immune unresponsiveness to antigens encountered in the gut.

oral tolerance

3 multiple choice options

select all that apply:

what happens with low doses of food antigen?

1. dendritic cells in the gut sample antigens from food

2. these DCs travel to gut-associated lymph nodes and trigger Treg cell development

3. Tregs promote immunological tolerance to food

select all that apply:

what happens with high doses of food antigen?

1. large or unprocessed food antigens might leak into tissues

2. large antigens get presented by APCs without co-stimulation

3. T cells become anergic or undergo apoptosis.

when tissue damage spills __________________ cell contents (like DNA or histones) into places they're not supposed to be seen by the immune system...things can go left.

internal

3 multiple choice options

intracellular components are normally hidden. but tissue damage releases them—think injury, infection, trauma. if these contents aren't cleared fast, they ____________________ → the immune system flags them as "danger."

accumulate

3 multiple choice options

triggers innate immunity, which hands it off to adaptive immunity—and now you're at risk of developing autoimmunity.

damage-associated molecular patterns

3 multiple choice options

the pathogen expresses an epitope that looks like a self epitope. leads to cross-reactivity: the immune system targets the pathogen, but accidentally hits self-tissue.

molecular mimicry

3 multiple choice options

select all that apply:

what are some clinical examples of molecular mimicry?

1. rabies vaccine

2. rheumatic fever (strep)

3. coxsackie virus

select all that apply:

why don't self-reactive lymphocytes in the periphery just die?

1. cross-reactivity might be helpful later

2. TLRs can wake them up during serious infections

3. survival > self-tolerance

self-reactive B cell is present but anergic (inactive). no inflammation, no infection = no problem.

healthy condition

3 multiple choice options

the self-reactive B cell gets activated (likely by TLRs or antigen mimicry). starts responding to self-epitopes →

autoimmunity

3 multiple choice options

a microbe shares a mimicking epitope. anergic B cell recognizes it and gets pulled into the fight.

PAMPs (pathogen-associated molecular patterns) activate TLRs → boost immune signaling.

infection

3 multiple choice options

high inflammation + strong TLR signaling = full activation of previously anergic, self-reactive B cells. these now attack host tissue too → full-blown autoimmunity.

fulminant infection

3 multiple choice options

infection and inflammation can flip the switch on self-tolerance and awaken autoimmunity through bystander activation or _________________.

mimicry

3 multiple choice options

~2/3 of autoimmune disease cases in the U.S. are ___________________. they show immune responses skewed toward TH1, which promotes cell-mediated immunity and inflammation.

female

3 multiple choice options

___________________ is a rare outlier—90% of patients are male. it's linked to HLA-B27 and TH17 pathways (not TH1-dominant).

ankylosing spondylitis

3 multiple choice options

many _________________ are associated with autoimmunity (not always causative).

genes

3 multiple choice options

select all that apply:

what are the big categories to classify autoimmune disease?

1. organ-specific

2. systemic

attacks one organ. targeted antibodies and local pathology. examples: Hashimoto's, type 1 diabetes, Graves'

organ-specific autoimmune disorders

1 multiple choice option

attacks multiple organs/tissues. often multiple autoantibodies involved. examples: SLE, rheumatoid arthritis, multiple sclerosis

systemic/organ non-specific autoimmune disorders

1 multiple choice option

select all that apply:

what is the pathophysiology of Hashimoto's thyroiditis?

1. autoantibodies + TH1 T cells attack thyroid antigens

2. macrophages + plasma cells infiltrate the thyroid

3. leads to inflammation and tissue destruction

4. over time → hypothyroidism and goiter

CTLs, macrophages, and autoantibodies attack insulin-producing β-cells in the islets of Langerhans.

type 1 diabetes mellitus

1 multiple choice option

select all that apply:

what is the pathophysiology of type 1 diabetes?

1. cytokine storm from immune cells → β-cell death

2. autoantibodies aid destruction via ADCC or complement

3. leads to absolute insulin deficiency

one of the few autoimmune diseases where the antibodies activate a receptor (instead of blocking or destroying it).

Graves' disease

3 multiple choice options

select all that apply:

what is the pathophysiology of Graves' disease?

1. autoantibodies target the TSH receptor on thyroid cells

2. stimulating antibodies mimic TSH, continuously triggering thyroid hormone production

3. no negative feedback loop so the thyroid keeps over producing hormone

symptoms: heat intolerance, weight loss, tachycardia, anxiety, bulging eyes (ophthalmopathy = thyroid eye disease)

hyperthyroidism

3 multiple choice options

select all that apply:

what is the pathophysiology of myasthenia gravis?

1. autoantibodies target acetylcholine receptors at the neuromuscular junction

2. antibodies block ACh binding and can also destroy AChRs via complement

3. ↓ muscle contraction → muscle weakness, especially in face/eyes

autoantibodies block or remove AChRs → no muscle activation.

myasthenia gravis

3 multiple choice options

a T cell–mediated attack on the CNS, specifically the myelin sheath that insulates neurons.

multiple sclerosis

3 multiple choice options

select all that apply:

what is the pathophysiology of multiple sclerosis?

1. trigger (unknown) allows immune cells to cross the blood-brain barrier

2. autoreactive TH1/TH17 T cells recognize myelin antigens in the CNS

3. microglial cells present antigens on MHC II, further activating T cells

4. cascade of inflammation, complement activation, cytokine release → leads to demyelination of neurons

1️⃣ trigger opens BBB.

2️⃣ T cells enter brain → meet microglia → recognize CNS antigens.

3️⃣ massive inflammation, cytokines, and antibodies ramp up.

4️⃣ demyelination occurs → disrupted nerve conduction → symptoms.

multiple sclerosis

3 multiple choice options

select all that apply:

what are some multiple sclerosis symptoms?

1. optic neuritis

2. muscle weakness, spasticity

3. loss of coordination

4. sensory disturbances

genetic/inherited conditions. usually present early in life, often before age 1-2. most affect either B cells, T cells, both, or innate components like phagocytes or complement.

primary immunodeficiencies

1 multiple choice option

acquired due to environmental factors like HIV/AIDS (targets CD4+ T cells), chemotherapy/radiation (suppresses bone marrow), severe burns, malnutrition, or chronic diseases

secondary immunodeficiencies

1 multiple choice option

prevalence of primary immunodeficiencies:

_____________________: 50% — most common.

combined B + T cell: 20% — like SCID.

phagocytic defects: 18% — like CGD.

cellular (T cell): 🔴 10%.

complement deficiencies: just 2% — rare, but associated with recurrent Neisseria infections.

humoral (B cell)

3 multiple choice options

primary immunodeficiencies are often caught by ___________________ based on a pattern of recurrent or weird infections.

pediatricians

3 multiple choice options

select all that apply:

what are some red flags for primary immunodeficiencies?

1. recurrent or hard-to-treat infections

2. failure to thrive

3. recurrent pneumonia, ear infections, sinusitis

4. deep abscesses

5. family history of immune disease

6. swollen lymph nodes or splenomegaly

example: SCID (severe combined immunodeficiency)

affects both cell-mediated and humoral immunity. patients are extremely vulnerable to infection and often require bone marrow transplants. also includes T-cell defects that indirectly affect B cells (since T cells help B cells activate and class switch).

combined immunodeficiencies (T + B cell)

3 multiple choice options

example: Hyper-IgM syndrome

usually caused by a CD40L mutation on T cells, which prevents proper interaction with B cells. so B cells can't class-switch, and you get low IgG/IgA, high IgM. results in recurrent bacterial infections.

B-cell defects

3 multiple choice options

example: chronic granulomatous disease (CGD)

caused by defective production of reactive oxygen intermediates (ROI) in phagocytes. phagocytes can't kill bacteria → recurrent abscesses, especially with catalase-positive organisms.

classic CGD bugs: Staph aureus, Serratia, Aspergillus

diagnosis: Nitroblue tetrazolium test (now replaced by DHR flow cytometry)

innate immune defects

3 multiple choice options

David Vetter had _______________, one of the most well-known causes of SCID. it is essential for purine metabolism. without it, toxic metabolites like dATP accumulate and kill lymphocytes—especially T and B cells.

result: no adaptive immune system. to protect him, David was raised in a sterile "bubble" environment. he sadly died after an unsuccessful bone marrow transplant.

adenosine deaminase deficiency

3 multiple choice options

select all that apply:

how do you get a diagnosis for humoral immunodeficiencies?

1. measure serum antibodies (IgG, IgA, IgM)

2. check response to vaccines

3. flow cytometry to count B cells

4. if CD19, CD20, and CD22 are low or absent → strong evidence of B cell deficiency

select all that apply:

how do you get a diagnosis for cellular immunodeficiencies?

1. flow cytometry, but now look at T cell markers CD3, CD4, and CD8

2. skin test responses (like PPD/tuberculin)

3. in vitro stimulation

these rely on T cell-mediated immunity. a flat/no reaction = poor T cell function.

skin tests

3 multiple choice options

T cells are cultured with mitogens like PHA (phytohemagglutinin). if they don't proliferate or make cytokines → cellular deficiency.

in vitro stimulation

3 multiple choice options

low CD3, CD4, and CD8 →

T cell deficiency

3 multiple choice options

low CD19/CD20 →

B cell deficiency

3 multiple choice options

both B and T cells missing →

SCID

3 multiple choice options

normal counts, poor function →

check vaccine response or mitogen

3 multiple choice options

a 6-month-old infant presents with recurrent pneumonia, oral thrush, and chronic diarrhea. labs show extremely low T and B lymphocyte counts. which of the following is the most likely diagnosis?

severe combined immunodeficiency

3 multiple choice options

a patient has low serum IgG, IgA, and IgE, but elevated IgM. which defect is most likely?

hyper-IgM syndrome

3 multiple choice options

which of the following tests is best for assessing T cell number and subsets in a suspected primary immunodeficiency?

flow cytometry for CD3, CD4, CD8

3 multiple choice options

select all that apply:

what is the function of regulatory T cells in maintaining peripheral tolerance?

1. secreting TGF-β and IL-10

2. killing self-reactive T cells

3. soaking up IL-2 via high-affinity CD25

4. inhibiting dendritic cells via CTLA-4

oral tolerance is most effectively established at:

low doses of antigen, via induction of Tregs

3 multiple choice options

select all that apply:

what is molecular mimicry, and how does it cause autoimmunity?

1. molecular mimicry occurs when a pathogen expresses an epitope similar to a host antigen

2. the immune system mounts a response against the pathogen, but cross-reacts with self-tissues

a child with severe recurrent bacterial infections is found to have absent CD19 and CD20 positive cells. which type of immunodeficiency is this?

B cell

3 multiple choice options

select all that apply:

which cytokines are secreted by Tregs to suppress self-reactive T cells?

1. TGF-β

2. IL-10

which primary immunodeficiency involves failure of NADPH oxidase function in phagocytes?

CGD

3 multiple choice options

select all that apply:

what is the immunologic defect in DiGeorge syndrome?

1. DiGeorge syndrome is due to a 22q11.2 deletion, causing thymic hypoplasia → impaired T cell development

2. patients are vulnerable to viral, fungal, and intracellular infections