Immunologic and inflammatory disorders/ T cell development Flashcards
——————- :a variety of proliferative disorders ‘macrophages’ (= over-production of white blood cells = histiocytes)
Histocytosis
Histiocytes can lead to ———- and ———–formation
Histiocytes can lead to organ damage and tumour formation
Is Langerhans cell histocytosis a sytemic disease?
Yes
What are langerhans cells?
type of WBCs that help the body fight infections (provide immunity)
bulidup of langerhans cells in certain body parts will lead to?
tumours or organ damage
LCH in children vs Adults
children –> acute disseminated multisytem disease
Adults –> Indolent Single organ disease
* indolnet –> slowly growing
Piutuitary invlovlement in LCH in adults is assocaited w?
Diabetes Insipidus
Calssification of langerhans cell Histocytosis
1) Acute disseminated LCH (Letterer - Siwe ds)
2) Multifocal LCH- multifocal eosinophillic granuloma ( Hand-Schuller-Christian disease)
3) Unifocal LCH - Unifocal Eosinophilic granuloma
CF of Acute disseminated LCH (Lettere- Siwe disease)
- mainly occur before the age of 2
1) Cutaneous abnormalities are present in almost 80% of patients (trunk and scalp)
2) hepatosplenomegaly
3) lyphadenopathy
4) lung involvement
5) destructive osteolytic bone lesions
In Acute disseminated LCH (Letterer - Siwe disease), when extensive BM involvement occurs pateints present w?
1) anemia, thrombocytopenia
2) recurrent infection (otitis media, mastoiditis)
3) if untreated can rapidly be fatal
(with intensive chemotherapy 50%, 5 year survival)
where are Langerhan cells found
Skin, spleen, lungs, bone marrow, liver, lymph nodes, skull
in Chronic Unifocal LCH bony lesions may cause ———?
Otitis media
CF/Epi of Multifocal LCH (Multiple Eosinophilic granuloma)
Classic HSC triad : Calvarian bone defects , exophthalmus , DI
- Epi : 2-4 yrs
* Calvarian bone : skull
CF/Epi of Unifocal LCH - unifocal eosinophilic granuloma
- Epi: age 5-15 years
1) Solitary clavarial lesions - solitary lesion of skull / vertebra /rib / mandible/ femur / ilium / scapula
2) Asymptomatic/ tenderness
3) an indolent disease (relatively benign)
* if clavarial lesion extend to the nervous system theyll cause neuro sx
which type of Histocytosis is associated w/ Tobacco smoking
Pulmonary LCH X
(Uncommon intersitital lung disease)
Epi of Pulmonary LCH X
- intersitial lung disease ass. w/ Smoking (tobacco)
- Affects young adults
- benign, RARE
CF of Pulmonary LCH X
1) Nonproductive cough (56-70%)
2) Dyspnea (40%)
3) Fatigue (30%)
4) Weight loss (20-30%)
5) Chest pain (21%)
6) Spontaneous pneumothorax, which may be recurrent, is a classic presentation found in 10-20% of patients
7) Fever (15%)
8) Cystic bone lesions (4-20%): These may be painful and may predispose the patient to pathologic fracture
what makes up a granuloma?
collection of Organized macrophages (ask Histocytes)
most common cause of lung granulomas?
fungal infections that primarily affect the lungs
Granulomas are most often the result of an ——— and most frequently occur in the ————, but can occur in other parts of the body as well
Granulomas are most often the result of an infection and most frequently occur in the
lungs, but can occur in other parts of the body as well
Apart from infections, ——- conditions can also cause granulomas
Autoimmune systemic conditions
Examples of Autoimmune systemic conditions
SLE, rheumatid arthritis, scelroderma
chracteristics of a granuloma
1) inflammation
2) fungal infections in the lungs
3) Autoimmune systemic conditions
macrophages in granulomas are often referred to as ”————-“
macrophages in granulomas are often referred to as “epithelioid”
TURE/FALSE
Loosely dispersed macrophages are not considered to be granulomas
True
they must be organized
infections that are characterised by granulomas
1) TB
2) leprosy,
3) histoplasmosis, cryptococcosis, coccidioidomycosis,
blastomycosis and cat scratch disease
Non-infectious Granulomatous diseases
1) sarcoidosis,
2) Chron’s disease,
3) berylliosis,
4) granulomatosis with polyangiitis,
5) eosinophilic granulomatosis with polyangiitis,
6) pulmonary rheumatoid nodules
7) Wegener granulomatosis
———–: multisystem inflammatory disease, that manifests as non-caseating granulomas,
predominantly in the lungs and intra-thoracic lymph nodes
Sarcoidosis
CF of Sarcoidosis
1) Lupus pernio (painful skin sores on face)
2) Lesion on back, arms, neck, face and scalp
3) Enlarges lymph nodes (in chest near wind pipe adn lungs)
4) Scarring and granulomas in lung
5) Spleen enlargment
6) Heart complications (rare)
7) Conjuctival lesions and scleral plaques
8) Anterior/ posterior granulomatous uveitis (most frequent)
9) crackel sounds in the lungs
10) Erythema nodosum
11) Violaceous rash on the cheeks or nose (common)
One of the main featurs of Wegner’s granulomatosis (GPA)
* GPA - granulomatosis w/ polyngiitis
Vasculitis
CF of Granulomatosis w/ polyngiitis (Wegner’s ganulomatosis)
1) recurrent respiratory infection in Adults
2) upper and lower respiratory tract problems in children
3) Fevers, night sweats
4) Fatigue, lethargy
5) Loss of appetite
6) Weight loss
CF:
* Typical Saddle nose damage
* Sclerokeratitis
* Vasculitis
are features of?
Wegener’s Granulomatosis
= GPA granulomatosis w/ polyangiitis
cell mediated vs Humoral immune respose
- Cell mediated immunity (T cells)–> does not produce Ag specific Abs
- Humoral response (B cells) –> produces Ag-specific Abs
where does the development of T cells take palce
- produced in the Bone marrow
- mature in the thymus
Mature T cells leaving the thymus, are diverse in their specificities and are both —————-and restricted to ————-
Mature T cells leaving the thymus, are diverse in their specificities and are both tolerant to self and restricted to self-MHC
T cells undergo development in the ——— and migrate to the —————, where they are activated by foreign antigens
T cells undergo development in the thymus and migrate to the peripheral lymphoid organs, where they are activated by foreign antigens
developing T cells are called ———-
Thymocytes
the 2 events of T-cell development
1) Early thymocyte development –> T-cell receptor independent
2) Selection events –> T-cell receptor dependent
VERY early thymocyte development occurs in the ———–
Bone marrow
The 3 stages pf Thymocyte Development
1) Early thymocyte development
2) Positive and negative selection
3) Lineage commitment
Immature T-cells (progenitor cells) migrating from the BM to the Thymus [Express/ do not Express] Ag receptors/ CD4 or CD8 or CD3
Do not Express
In Early thymocyte development Cells go through a series of different stages, what are they?
1) Double negative (DN) no CD4 or CD8 expression CD4-CD8
2) Double positive (DP)—both CD4 and CD8 (TCR expressing
3) Recombination of TCR gene segments occurs in the DN stages
What is lineage commitment?
Its when selceted thymocytes mature to become SP (single positive) , Where thye either become CD4+ or CD8+ T cells
- Note:
this happens after positive and negative selection (so Thymocytes that have passed the +ve selection will undergo Lineage commitment)
* First DN –> DP –> SP
Selected thymocytes mature to become single positive (SP), where only CD4 or CD8 are expressed, this is known as?
Lineage Commitment
Exaplin what happnes during the selection events of Thymocyte development
Positive/ Negative selection satges :
1) Postive selection –> selection for those cells whose TCR respond to self-MHC
2) Negative selection –> selection against those cells whose TCR reacts strongly to self-peptide/MHC combinations
3) selected thymocytes (the ones passing positive selection) –> are realeased into the peripheral bloodstream
T-cell development in the cortex
1) DN: once they encounter the thymic environment they ———–
2) DN: ————- begins to rearrange
3) DN: those that have successfully rearranged β-chain form ———— , they proliferate and mature to ———
4) DP: initiation of ———– chain, if successful then ——— is expressed and cells are ready for the second stage of T cell development (———-)
1) DN: once they encounter the thymic environment they proliferate
2) DN: β-chain begins to rearrange
3) DN: those that have successfully rearranged β-chain form pre-TCR , they proliferate and mature to DP
4) DP: initiation of TCRα chain, if successful then TCR is expressed and cells are ready for the second stage of T cell development (selection)
————– ensures only one β-and α-chain are expressed per cell during the early thymocyte development
Allelic exclusion
Surface molecules expressed during development of T-cells (during the DN and DP stage)
RAG1/RAG2 and TdT
why is thymic selection necessary?
Randomly generated TCRs can recognize all possible MHC/peptide combinations–> dangerous (they will attack “self”)
- note:
i.e. recognize foreign MHC/peptides – not useful
i.e. recognize self MHC/self peptides – dangerous!!!!
i.e. recognize self-MHC forgein-peptide- useful
Positive selection ensures ————-
MHC restriction
how does positive selection ensure MHC restriction?
Selects thymocytes bearing T cell receptors (TCR) capable of binding self-MHC molecules, allowing the creation of a self-MHC restricted T cell repertoire
* repertoire : store/ collection
Negative selection ensures ————
Self-tolerance (Central tolerance)
Negative selection happens in the ———— and the ——– of the thymus and eliminates T cells that bind too strongly to self-MHC+ self peptide
(———————)
Negative selection happens in the cortex and the medula of the thymus and eliminates T cells that bind too strongly to self-MHC+ self peptide
(central tolerance)
cells involved in the +ve/-ve selection of thymocyte development
Cortical and medullary thymic epi cells, macrophages and DCs
Funtion of cortical and medullary thymic epi cells, macrophages and DCs?
1) Express MHC I and II
2) developing T cells interact w/ these cells through TCR-CD3
Cortical and medullary thymic epi cells, macrophages and DCs play important roles in the selection
* These cells express MHC I and II and developing T cells interact with them through their ————-
TCR-CD3
Developing T cells that can bind MHCs shift from —— to ——-
DP –> SP
* If the TCR can bind to an MHC class II molecule, it becomes a CD4+ cells
* The opposite happens if the TCR binds to an MHC class I molecule, it becomes a CD8+ cell
How are developing T cells checked against self- antigens that are not expressed in the thymus?
The thymus expresses and presents proteins from all the body, those are presented to —> AIRE, expressed by medullary thymic epithelial cells (mTECs), which eliminate autoreactive T cells –> preventing them from being released into the peripheral bloodstream
Maturation of T cells happens in the Thymus, in which part does final maturation occur
1) Thymic medulla or
2) Thymic cortex ?
Medulla
While most self-reactive T cells will be deleted in the thymus, a small population of these T cells will instead differentiate into ————
TREG cells
T regulatory cells (Tregs) belong to a subset of CD4+ T cells charcaterized by constitutive expression of ——–, —— and ——— transcription factor
They belong to a subset of CD4+ T cells characterized by constitutive expression of CD4, CD25 and FoxP3 transcription factor
What cytokines are secreted by Tregs?
IL-10 and TGF-β
fx of IL-10 and TGF-β
anti-inflammatory Cytokines released by Tregs (inhibit inflammation)
How do Tregs serve in peripheral tolerance?
when they leave the thymus they inhibit the fxn of escaping autoreactive T cells
