30-01-12
ALLERGY:
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GALECTIN-9: A SUPPRESSOR OF FOOD ALLERGY?
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Prevalence of food-induced allergy: 5% of children and 4% of adults.
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Some probiotics (bifidobacteria or lactobacilli) can prevent allergy by ↑ Th1.
Growth of bifidobacteria in GI flora can be achieved by diet with GOS and FOS.
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Galectin-9 is expressed by GI epithelial cells during inflammatory responses.
Synbiotics (GOS + FOS + Bifidobacterium breve) ↑ release of galectin-9.
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Antiallergic actions of galectin-9: ↑ Th1; ↑ Treg; binding and sequestration of
IgE (a heavily glycosylated Ig), preventing antigen-IgE complex formation.
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Soluble PRR with carbohydrate binding capabilities: ficolins, pentraxins and the
collagenous lectins (collectins). Galectins are beta-galactoside binding lectins.
GENE EXPRESSION IS DIFFERENTLY AFFECTED BY PIMECROLIMUS AND
BETAMETHASONE IN LESIONAL SKIN OF ATOPIC DERMATITIS:
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Corticosteroids: more potent anti-inflammatory effect, may impair restoration
of the skin barrier; main treatment for severe and acutely exacerbated AD.
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Pimecrolimus: long-term treatment and stabilization. Low penetration → side
effects limited to skin. Main targets: keratinocytes, LCs, and T cells.
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Calcineurin mediates calcium-dependent dephosphorylation of the
transcription factor nuclear factor of activated T cells (NFAT), which
translocates to the nucleus and stimulates cytokine genes, such as IL-2.
NEGATIVE PREDICTIVE VALUE OF SKIN TESTS TO NMBA:
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Specific IgE may not help in the evaluation of NMBA allergy.
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Skin tests are the cornerstone of the diagnosis of NMBA allergy and a positive
ST confirms allergy to the product, with a high sensitivity.
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The excellent predictive value of STs in our series was obviously biased by the
small number of patients (six).
PRACTICAL GUIDE TO SPT IN ALLERGY TO AEROALLERGENS: SOME CONCERNS:
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To cover 95% of sensitized children, the number of allergens needed are 12, 8
and 7 for preschool children (2–<6 year), school children (6–<12 year) and
adolescents (12–18 year), respectively. SE REQUIEREN MÁS AEROALÉRGENOS
EN LAS PRUEBAS A NIÑOS DE 2-6 AÑOS.
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10–20% of preschool children (2–<6 year), 30–60% of school children (6–<12
year) and 50–70% of adolescents (12-18 year) were sensitized to one of 30
aeroallergens tested. Low possibility of a positive result and pain in a young
child are major concerns for performing SPT routinely → postpone for elder
age or replace with sIgE measurement. ¿USAR PRICK DE RUTINA EN <6 AÑOS?
SLIT: MODE OF ACTION AND ITS RELATIONSHIP WITH THE SAFETY PROFILE:
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SLIT-associated immune responses include ↑ allergen-specific Th1 and T regs.
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60% of patients receiving SLIT experience mild, transient local reactions in the
oral mucosa, which rarely need dose reduction or treatment interruption.
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In contrast to SCIT, SLIT appears to elicit mucosal IgA responses, which may
contribute significantly to tolerance induction.
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SLIT requires 50–100 times more allergen than SCIT to achieve similar efficacy.
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In healthy human oral tissues, the main APCs are Langerhans cells (located in
the mucosa itself) and myeloid DCs (located along the lamina propria). These
DC subsets are tolerogenic; after migration to draining cervical lymph nodes,
they support the induction of IFN-γ/IL-10-producing Th1 cells and T regs.
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SLIT: most allergen in contact with oral tissue is captured within 30-60 min by
tolerogenic DCs before it reaches MCs or eosinophils.
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SCIT: higher risk of direct contact between allergen and pro-inflammatory
basophils, Th2 cells, myeloid or plasmacytoid DCs whose effector immune
responses are associated with the release of proinflammatory mediators.
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Mast cells are closer to the mucosal surface in lingual tissues than in other oral
tissues → one frequently reported SLIT adverse reactions is lingual edema.
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One SLIT-related serious adverse reaction per 384 treatment years: asthmatic
reactions; abdominal pain/vomiting; edema of the uvula; urticaria.
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11 nonfatal cases described as “anaphylaxis”. These case reports do not
represent standard practice in SLIT (non-standardized extracts, allergen
mixtures, rush protocols, overdose, serious adverse reactions with SCIT).
Around one case per 100 million SLIT administrations.
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Anaphylaxis suspicion → immediate treatment with IM epinephrine.
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THE ROLE OF VIT D IN THE IMMUNOPATHOGENESIS OF ALLERGIC SKIN DISEASES:
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25(OH)D: stable, half life: 3 weeks in serum, most accurately represents total
vitamin D stores in the body.
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VDR has been identified on nearly all cells of the immune system.
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(1) Binding of 1,25(OH)2D to VDR, a nuclear hormone receptor; (2) VDR
dimerization with the retinoid X receptor (RXR); (3) binding of 1,25(OH)2DRXR-VDR to vitamin D response elements (VDRE) on DNA.
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It is difficult to determine if low vit D levels contributed to development of AD,
or if damage of skin from AD led to low vit D absorption from the sun.
ANNALS OF ALLERGY AND CLINICAL IMMUNOLOGY:
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ALLERGEN OF THE MONTH—RICE:
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Polen de arroz: asma, rinitis.
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Ingestión de arroz o inhalación de vapor: asma, rinitis, conjuntivitis, dermatitis
atópica, anafilaxia.
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Rice millers’ syndrome in Malaysian workers: rhinoconjunctivitis, asthma,
eosinophilia, and pulmonary infiltrates; attributed to rice husk dust exposure;
LPS in rice husks may up-regulate eosinophilic responses.
COST, UTILIZATION, AND PATTERNS OF MEDICATION USE ASSOCIATED WITH
CHRONIC IDIOPATHIC URTICARIA:
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Mean age: 36 years old; 56% followed by primary care physicians, 14% by
allergists and 5% by dermatologists.
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Allergic rhinitis was diagnosed in 48%, asthma in 21%, atopic dermatitis in 8%,
anxiety in 10%, depression in 10%.
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76% used prescription antihistamines, 54% used oral corticosteroids, 24% used
montelukast, 9% used oral doxepin and 1% used cyclosporine.
DO HYPOALLERGENIC CATS AND DOGS EXIST?
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Allerca Lifestyle Pets market “hypoallergenic” cats and dogs. Allerca states that
these pets allow millions of people with feline or canine allergies to have pets.
Now, in its 7th to 8th year of operation, the price tag is as high as $7,950 for a
hypoallergenic dog and $6,950 to $22,950 for a hypoallergenic cat.
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Allerca says that their pets produce lower allergenic quantities of pet dander
(Fel d 1 and Can d 1 from cats and dogs) through gene mutations. Minor
allergens (eg, Fel d 2, Fel d 3, Fel d 4) also sensitize pet-allergic individuals.
Therefore, selective breeding of these animals would be unlikely to result in
complete benefit for their affected owners.
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90-95% of cat-allergic patients have specific IgE to Fel d 1.
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No published literature indicates that “hypoallergenic” cats and dogs exist.
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Lifestyle modifications to reduce exposure to pet allergens: (1) remove the pet
from the home; (2) bath the pet twice per week (more effective for dogs).
GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS IN ASTHMA AND ALLERGY:
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Advantages of candidate gene approach: detection of genes with smaller
effects in sample size compared with linkage studies; easier recruiting of
unrelated cases and controls (linkage studies need family recruiting).
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Genes identified by candidate gene approach: IL-4, IL-4R, IL-13, β2-adrenergic
receptor, HLA DQB1, TNF, LT-α, FcRεI, ADAM33.
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Genes identified by Genomewide Linkage Studies: ADAM33, CH13L1, DPP10,
HLA-G, PHF11, PTGDR and PLUAR.
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Genes identified by GWAS: ORMDL3, GSDML, IL1RL1/IL18R, HLA-DQ, IL33,
SMAD3, IL2RB, DENND1B, CH13L1, PDE4D, PRE4D, RAD50-IL13, TSLP, PYHIN1.
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Copy Number Variations is an alteration of the DNA of a genome that results in
the cell with an abnormal number of copies on 1 or more sections of the DNA.
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Epigenetic changes can remain through cell divisions for the remainder of the
cell’s life and can also last for multiple generations.
MULTIPLE DRUG INTOLERANCE SYNDROME (MDIS):
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MDIS: 3 or more unrelated drug class “allergies”; 2% of patients.
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MDIS is in part iatrogenic, associated with overweight elderly women taking
several drugs. Urticarial syndromes only explain a small fraction of cases.
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MDIS is associated with anxiety, but not predominately with IgE-mediated
allergy or life-threatening illness. MDIS can be managed by medication
avoidance and judicious rechallenge.
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Multiple drug “allergy” is relatively uncommon in children and most ADRs in
children are associated with antibiotic use.
CURRENT OPINION IN IMMUNOLOGY:
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ANTIGEN PRESENTATION EVENTS IN AUTOIMMUNE DIABETES:
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The intra-islet APC are central cells in diabetogenesis by presenting beta cell
derived antigens and by modulating the localization of T cells into the islets.
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Under normal conditions, β-cells have low levels of MHC I and do not express
MHC II. Presentation of β-cell antigens to autoreactive CD4 T cells involves the
transfer of antigenic material from the β-cells to the APC.
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The PLN drain the acinar component of pancreas except for the islets, which
lack lymphatic circulation. PLN also drain segments of the intestine, a relevant
issue regarding the influence of the microbiome in diabetes.
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The islet DC is a central cell in diabetogenesis, it is heavily charged with class II
pMHC complexes due to constitutive uptake of β-cell granules. The islet DC is
instrumental in the initial sensitization, most likely by moving to the PLN. Most
DCs were in tight association with the blood vessels.
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Inflammation → more migration from islet DCs to PLN → priming of T cells.
AUTOANTIGENESIS: THE EVOLUTION OF PROTEIN MODIFICATIONS IN AUTOIMMUNE
DISEASE:
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The term ‘autoantigenesis’ is defined as the changes that arise in self-proteins
as they break self-tolerance and trigger autoimmune B and/or T cell responses.
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Between 50 and 90% of our proteins acquire post-translational modification to
enhance their biological action. Some post-translational modifications can
create new self-antigens.
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Post-translational modifications (PTMs) in self-antigens may affect the analyses
of B and T cell specificity, current diagnostic techniques, and the development
of immunotherapies for autoimmune diseases.
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Classical biochemistry tells us that 20 amino acids make up most proteins in
nature. Closer examination, however, reveals a number that far exceeds those
20 original structures. Indeed, when PTMs are considered, more than 140
unique amino acids compose protein.
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PTMs can arise either by enzymatic modification, as is the case of N-linked
glycosylation or phosphorylation, or can occur spontaneously, as is the case in
the deamidation of asparagine to aspartic acid or isoaspartic acid.
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B CELLS AND AUTOIMMUNITY:
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Checkpoint mayor de tolerancia ocurre durante transición: linfocitos pre-B
pequeños (tienen receptor pre-B, son IgM– pero ya recombinan cadena ligera
κ) → linfocitos B inmaduros.
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Linfocitos B inmaduros: primeras células en expresar BCR; expresan cadena
ligera κ (cadena λ es generada después) y un heterodímero Igα/Igβ; son IgD–.
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The presence of a heptamer (CACAGTG) containing RS (recombining sequence)
downstream of Cκ permits the deletion of the κ locus during receptor editing
and appears to be crucial for induction of λ light chain gene rearrangement. In
humans the sequence similar to the RS element is called κ deleting element or
KDE. Defects in receptor editing occur in humans with lupus and type I DM.
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While multivalent antigens appear to primarily mediate receptor editing,
soluble antigens mainly induce anergy. Some deletion of self-reactive B cells
also probably occurs in immature and transitional B cells in vivo.
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Deletion may be crucial when all editing options are exhausted, and may be
the major mechanism that drives pre-BCR censoring when most of the selfrecognition is mediated by the heavy chain alone.
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Checkpoint más temprano de tolerancia: pre-BCR censoring. Ocurre durante la
transición pro-B → pre-B. Self-ligands interact with some pre-BCRs → deletion.
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Pre-BCR signaling resembles the analogous process initiated by auto-reactive
BCRs: both categories of receptors initiate light chain gene rearrangement,
primary light chain gene rearrangement in the case of the pre-BCR and
secondary rearrangements when signals are initiated by auto-reactive BCRs.
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Immature B cells migrate from the bone marrow to the spleen as part of the
maturation process although some maturation can continue in the BM.
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T-1 cells: splenic cells with phenotype similar to immature B cells (IgM+IgDCD23-CD21loCD93hiCD24hi); they are recent emigrants from the bone marrow
and are assumed to have not yet entered the follicular niche.
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T-2 cells: splenic B cells with markers of recent generation (CD93hiCD24hi); but
they are CD23+ and begin to express IgD (they can be IgD- or IgD+); they
represent recent emigrants that have entered the follicular niche and have
acquired the ability to recirculate. T-1 and T-2 cells that encounter self-antigen
that is multivalent may be clonally deleted.
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Immature, T-1, and T-2 cells that are repeatedly stimulated by high affinity selfantigen may be anergized and acquire an IgDhiIgMloCD93+ T-3 cell phenotype.
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IL-21 secreted by TFH cells → high levels of Fas and low levels of Bim in GC B
cells → B cells are prone to apoptotic death by mitochondrial pathway and
death receptor signaling. High affinity B cells may be induced to express c-FLIP,
an antagonist of caspase-8, either though the BCR or because they more
readily capture and present antigen for T cell help. These cells may thus not be
killed by FasL expressed on TFH cells. Some regulation of B cells in the germinal
center may be mediated by Treg-like TFH cells that express CXCR5.
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In human subjects the IgG+CD27+ presumed class switched memory B cell
population exhibits both some auto-reactivity as well as some polyreactivity
even in healthy subjects, suggesting that a break in tolerance may occur during
the germinal center reaction. Since this polyreactivity is observed in healthy
subjects it is likely that this self-reactive IgG is not pathogenic.
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Bregs, as commonly defined, overlap with cells that are precursors of marginal
zone B cells. The absence of MZP B cells is always correlated with an absence
of MZ B cells. Mice with engineered genetic mutations in which MZP and MZ B
cells are absent do not present with florid autoimmunity — certainly any
comparison of relevance in a functional sense with Tregs would be premature.
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Although DCs are the key APCs for the initiation of CD4+ T cell activation, B
cells are required for subsequent activation and memory generation.
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CD20 is expressed on mature and memory B cells but not on long-lived plasma
cells. Rituximab cannot typically deplete these long-lived cells; the secretion of
pathogenic auto-antibodies might not be attenuated by this biological therapy.
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LES pathogenesis is driven by chromatin derived auto-antigens that can engage
BCR and activate endosomal TLR; auto-antigen specific B cell differentiation to
long-lived plasma cells may occur more readily in LES than in other disorders.
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Rituximab has also been reported to promote the expansion of Tregs.
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BAFF/BLyS: growth factor for B cells after the T-1 stage, essentially in the
follicular milieu. BAFF is also required for the differentiation in the spleen of
transitional and FO-II cells into MZP B cells and MZ B cells. High levels of BAFF
can contribute to autoimmune disease by preventing the tolerization of selfreactive B cells thus allowing them to enter B follicles and survive. But
Belimumab and Atacicept did not have good effect in autoimmune diseases.
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Immunodeficiencies → autoimmunity: Robust BCR signaling is required for
receptor editing, clonal deletion and anergy → defective BCR signaling could
contribute to autoimmunity. In milder cases of XLA, attenuated BCR signaling
because of defective Btk molecules results in a breakthrough of self-reactive B
cells at the bone marrow and early peripheral B cell tolerance checkpoints.
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Hypomorphic Rag mutations causing Omenn syndrome → defective receptor
editing and elevated BAFF because of B cell depletion → autoimmunity.
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Patients with bare lymphocyte syndrome, X-linked hyper-IgM and AID deficit
have problems in peripheral B cell tolerance and autoimmunity.
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CD22/Siglec-2 binds to sialic acid containing N-glycans → ITIM phosphorylation
by the Lyn tyrosine kinase → recruitment and activation of the SH2 domain
containing tyrosine phosphatase SHP-1 → attenuation of BCR signalling.
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The overall evidence suggests that the SIAE/Siglec pathway maintains
peripheral tolerance by setting a threshold for B cell activation, and
presumably prevents weak self-antigens from drawing cognate B cells into T–B
collaboration and the risk of somatic mutation. SIAE, Siglec, Lyn and SHP-1 may
function primarily to maintain B cells in a state of clonal ignorance.
DIFFERENTIAL PROCESSING OF SELF-ANTIGENS BY SUBSETS OF THYMIC STROMAL
CELLS:
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Thymic cortical epithelial cells (cTECs) are specialized APCs that promote the
positive selection of developing thymocytes while medullary thymic epithelial
cells (mTECs) and thymic dendritic cells (tDCs) induce central tolerance to selfantigens.
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cTECs express a unique set of proteases involved in the generation of selfpeptides presented by pMHC and consequently may express a unique set of
pMHC complexes. Conversely, the stromal cells of the medulla developed
several mechanisms to mirror as closely as possible the constellation of selfpeptides derived from peripheral tissues.
THE MANY FACES OF TH17 CELLS:
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Th17 cells are more plastic than Th1 cells: ‘Classical’ Th17 cells are less stable
and switch over into IFN-g producers relatively easily in vivo. ‘Alternative’ Th17
cells – due to exposure to IL-23 – are more ‘terminally differentiated’ and
maintain a stable IL-17 production, but often co-produce IFN-g in target organ.
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Th17 cells may produce IL-10; exposure of Th17 cells to IL-23 diminishes IL-10
production; TGF-b promotes IL-10 production. The transcription factor c-Maf is
probably an important driver for IL-10 production in Th17 cells.
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Th17 cells seem to be more susceptible than other T cell subsets to inhibition
by IL-10 signaling. In the absence of IL-23, Th17 cells may eventually start
producing IL-10 in order to control themselves and prevent damage.
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Th17 cells are known to produce IL-21 and depend on it for self-amplification.
IL-21 might be associated with ‘classical’ more regulated Th17 cells rather than
‘alternative’ more pathogenic Th17 cells.
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TGF-b suppresses GM-CSF production in Th17 cells; IL-1b and IL-23 promote
GM-CSF production. GM-CSF induces APCs to produce IL-6 and IL-23, and
attracts inflammatory cells – primarily macrophages. GM-CSF greatly
contributes to the pathogenicity of ‘alternative’ Th17 cells.
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A great opportunity for the inhibition of Th17 cells has arisen through the
discovery of synthetic ROR-γt specific inhibitors such as Digoxin and SR1001.
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY:
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A RAPID SCREENING METHOD TO DETECT AD EDA-ID SYNDROME:
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Patient: 5-month male; dysmorphisms; ↓ body T° regulation due to anhidrosis;
many infections from 1st month (hepatitis with CMV, enteritis with rotavirus,
bronchiolitis with RSV, bacterial pneumonia, UTI, otitis media). No family
history. ↑ IgA (751 mg/dL, normal = 10-56). Low lymphocyte proliferation.
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We used a rapid screening method for IRAK4 deficiency using patient’s blood
cells. Flow cytometric analysis of intracellular TNF-α production in CD14+ cells
after 4 hours of LPS stimulation showed a substantially lower proportion of
CD14 and TNF-α double-positive cells in the patient than in healthy subjects.
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The serine residues of the N terminus of IkBα are important phosphorylation
sites. Phosphorylation leads to degradation of IkBα and release of active NFkB. If these residues are substituted or deleted, IkBα cannot be inactivated by
IKK (hypermorphic effect of N terminus–truncated IkBα protein).
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NF-kB is an essential component of immune responses → some EDA-ID
patients have combined T-cell dysfunction. NEMO deficiency was recently
reported to be one of candidate deficiencies of MSMD syndrome.
A SUSPICION OF ANTIBIOTIC ALLERGY IN CHILDREN IS OFTEN INCORRECT:
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Antibiotic allergy: (1) IgE assays: low sensitivity and specificity; (2) IDR can be
used to demonstrate a type I reaction, but not a delayed reaction, and confirm
a high number of false-negative reactions; (3) DPT is the gold standard.
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Allergy in 14% of suspected cases → NO ASUMIR ALERGIA ANTES DE TIEMPO.
ADVANCES IN BASIC AND CLINICAL IMMUNOLOGY IN 2011:
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An increase in TH17 cells in patients with IPEX syndrome was demonstrated.
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PNP has an essential role in the survival of double-positive thymocytes.
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Null ATM mutations: earlier onset of cancer and lower life expectancy.
Hypomorphic ATM mutations: respiratory infections are 1st cause of mortality.
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PIDs known to be most associated with increased occurrence of malignancies
and viral infections: XLP; IL-2–inducible T-cell kinase (ITK) deficiency; SCID;
epidermodysplasia verruciformis; WHIM syndrome; AR-HIES; XLA; CVID.
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Glomerulonephritis occur in patients with CD19 deficiency; CVID in adult
patients may present as HSV–induced encephalitis.
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XLA: accelerated decrease in lung function compared to CVID, partially
attributed to increased years of smoking and the presence of bronchiectasis.
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A PID syndrome characterized by CMC, CMV infection and autoimmunity was
reported to be associated with the amino acid sequence variant L412F of TLR3.
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CHH: reduced number of naive T cells and increased apoptosis of T cells.
Hypomorphic mutation in IL2RG: CD4 T lymphopenia and infections.
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2 patients with reticular dysgenesis developed myelodysplastic syndrome after
a myeloablative HLA-haploidentical HCST that resulted in mixed chimerism.
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Case reports showed hypogammaglobulinemia and HLH in a 3-year-old boy
with a mutation in FAS gene, reminding us the heterogeneity of ALPS.
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Screening for ADA deficiency by tandem mass spectrometry to detect adenine
metabolites in Guthrie cards may be more cost-effective over TREC analysis.
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Two PID (Dock8 deficiency and an early-onset form of monoMAC), were
successfully treated with myeloablative HLA-identical HSCT protocols.
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An adipose tumor with incomplete correction of purine metabolism was
reported 3 years after gene therapy in a patient with ADA-SCID, underscoring
limitations of HSC–based gene therapy for treatment of multiorgan disease.
ADVANCES IN MECHANISMS OF ASTHMA, ALLERGY, AND IMMUNOLOGY IN 2011:
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Allergic disease results from the subversion of the innate immune system by
allergens and associated chemicals. Influencing factors: genetics, age and
route of exposure, climate, pollution, commensal diversity, stress.
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Transcutaneous sensitization to allergens might be a critical step for atopy.
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Sensitization to toluene diisothiocyanate (TDI) requires oxidative stress. TDI is
the most frequent cause of occupational asthma.
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2 years of IT to grass pollen → specific IgG → blocking and tolerance.
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SLIT has later onset of action than SCIT. There is a potential attractiveness for
an IT regimen composed of early SCIT followed by the addition of SLIT.
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Genetically engineered allergens can ↑ efficacy and safety in IT.
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Facilitated antigen presentation: soluble IgE-allergen complexes are captured
and internalized by CD23 on B cells → presentation of allergen peptide to
CD4+ T cells → activation and proliferation.
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Tick bites → IgE antibodies to oligosaccharide galactose-α-1,3-galactose (α-Gal)
→ delayed-onset anaphylaxis after ingestion of beef, lamb, or pork.
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Period2 gene might explain circadian influence in anaphylaxis by controlling
the rhythm of adrenal secretion of GCs, mast cell responses to GCs, or both.
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SlanDCs program the TH17/TH1 cells that contribute to the pathogenesis of
psoriasis by secreting IL-17, IL-22, TNF, and IFN- γ.
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Serotonin, a prominent product of mast cells and platelets, acts through the
organic cation transporter 3 to suppress the secretion of IL-4 by basophils.
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Calcitonin gene-related peptide and VEGF induce vasodilatation and increase
permeability during late-phase cutaneous reactions.
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High-atopic-risk infants: significantly lower cord blood CD34+ cell expression of
TLR2, TLR4, and TLR9.
AUTOIMMUNE REGULATOR (AIRE) CONTRIBUTES TO DECTIN-1–INDUCED TNF-α
PRODUCTION AND COMPLEXES WITH CASPASE RECRUITMENT DOMAIN–
CONTAINING PROTEIN 9 (CARD9), SPLEEN TYROSINE KINASE (SYK), AND DECTIN-1:
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PBMCs from patients with APECED syndrome or AIRE-deficient cell lines had
reduced TNF-α response after Dectin-1 ligation but in part used a Raf-1–
mediated pathway to preserve function. AIRE formed a transient complex with
the known Dectin-1 pathway components phosphorylated Syk and CARD9
after receptor ligation and localized with Dectin-1 at the cell membrane.
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AIRE can participate in the Dectin-1 signaling pathway, indicating a novel
extrathymic role for AIRE and a defect that likely contributes to fungal
susceptibility in patients with APECED syndrome. AIRE might also be involved
in Dectin-2 signaling. Syk is a likely candidate to be affected by AIRE deficiency.
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Signaling after Dectin-1 ligation uses 2 independent pathways: Syk and Raf-1.
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APECED: we propose that blunted AIRE-mediated Dectin-1 signaling would
create a milieu in which reduced Dectin-1–directed anticandidal inflammation
and clearance at mucosal surfaces enables a tonic anticandidal response with
prolonged (but insufficient) production of IL-17 in response to chronic Candida
species infection. In the context of AIRE deficiency, this could potentially
facilitate the generation of the anti–IL-17 autoantibodies.
CD27 EXPRESSION ON ALLERGEN-SPECIFIC T CELLS: A NEW SURROGATE FOR
SUCCESSFUL ALLERGEN-SPECIFIC IMMUNOTHERAPY?
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High ratio of specific to total serum IgE correlated with effectiveness of IT.
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Tolerant subjects: Aln g 1–specific CD4+ T cells express CD27 (central memory
phenotype), CCR7 and TH1-associated markers, such as CXCR3 and IFN-g.
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Allergic subjects: Aln g 1–specific CD4+ T cells fall into 2 subsets, with the
smaller subset expressing and the larger subset lacking CD27 (terminally
differentiated effector cells; CCR7-CCR4+CRTH2+; express IL-4, IL-5 and IL-13).
This CD27- population cells was preferentially deleted after successfully
completed IT, whereas their TH1-like CD27+ counterparts prevailed.
Interaction of the costimulatory molecule CD27 on the T cell with its ligand,
CD70, on DCs has been implicated in supporting TH1 differentiation. CD70
expression is restricted to TH1 cells and might serve to amplify TH1-instructing
signals in T/T-cell interactions through a positive feedback mechanism.
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FUNGAL DISEASE OF THE NOSE AND PARANASAL SINUSES:
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Rhinosinusitis: 13% of the population. Fungi are ubiquitous in nature, and
exposure to the sinonasal and respiratory epithelium is thus unavoidable.
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Noninvasive disease: asymptomatic fungal colonization, fungus balls, and
allergic fungal rhinosinusitis.
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Invasive disease: indolent chronic rhinosinusitis, granulomatous fungal
sinusitis, and acute fulminant fungal rhinosinusitis.
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Topical or systemic antifungal therapy plays a limited role in the treatment of
noninvasive infection; these agents can play a critical role and should be
partnered with surgery in patients with invasive fungal rhinosinusitis.
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Saprophytic fungal infestation/fungal colonization: patients are typically
asymptomatic; anatomic or injury predisposition; not always needs treatment.
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Saprophytic fungus ball: predominantly caused by Aspergillus. Previously
termed mycetoma or aspergillomas, designations should include: localization +
fungus ball ± causative fungus (eg, maxillary sinus fungus ball caused by
Aspergillus fumigatus). Diagnosis: clinical history (chronic nasal discharge,
nasal obstruction, headache, facial pain, cacosmia, asymptomatic), CT
(heterogeneous opacities with discrete calcification or densities in the sinus,
maxillary sinus > sphenoid sinus); accumulation of fungal hyphae without
tissue invasion, eosinophil predominance, granuloma or allergic mucin.
Cultures positive in <1/3 of patients despite obvious fungal elements on
histopathologic examination in >90% of those affected. Treatment: surgery;
antifungal treatment is not warranted.
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Allergic fungal rhinosinusitis (eosinophilic fungal rhinosinusitis, eosinophilic
mucin rhinosinusitis): CRS (>12 weeks) + sinus opacification with allergic mucin
(thick mucus from tan to brown or black). Agents: Aspergillus, Alternaria,
Cladosporium, Bipolaris, Curvularia. Inflammation can expand and produce
sinus expansion, mucocele formation and bone erosion, despite a lack of tissue
invasion. Proptosis, diplopia, and vision loss have been described. HLA is
involved. Intraoperatively specimens are more reliable for fungal culture.
Treatment: surgery → OCS; systemic antifungals are not useful; IT may help.
FUNGI AND ALLERGIC LOWER RESPIRATORY TRACT DISEASES:
•
Mold sensitivity, particularly to A alternata and C herbarum, has been
associated with the development, persistence, and severity of asthma.
•
Allergic rhinitis and asthma both have been associated with exposure to fungal
contamination in homes.
•
Sensitivity to Aspergillus fumigatus has been associated with severe persistent
asthma in adults. ABPA is caused by A fumigatus and is characterized by
exacerbations of asthma, recurrent transient chest radiographic infiltrates,
coughing up thick mucus plugs, peripheral and pulmonary eosinophilia, and
increased total serum IgE and fungus-specific IgE levels.
•
ABPA is the most common form of allergic bronchopulmonary mycosis
(ABPM); Candida, Penicillium and Curvularia species are also implicated.
•
The term severe asthma associated with fungal sensitization (SAFS) has been
coined to illustrate the high rate of fungal sensitivity in patients with persistent
severe asthma and improvement with antifungal treatment.
•
Genetic risks identified in patients with ABPA include HLA association and
certain TH2-prominent and cystic fibrosis variants.
•
Both ABPA and SAFS might respond to antifungal therapy, as well as
corticosteroids. Omalizumab or IT may be helpful.
•
Designation of ABPA-seropositive (ABPA-S) can be used to classify asthmatic
patients who meet criteria but lack central bronchiectasis (ABPA-CB).
•
At the time of radiographic exacerbation, the presence of sputum or blood
eosinophilia is suggestive of ABPA, especially if total IgE concentration has ↑.
Plasma levels of thymus and activation-regulated chemokines (CCL17) might
be a better marker for ABPA than IgE levels, especially for exacerbations.
•
The conidia of A fumigatus, Penicillium and Cladosporium species are
nonreactive, only inducing an immune response when germination is initiated.
•
It has been reported that SPTs are more sensitive but less specific than serum
sIgE tests to diagnose allergic sensitization in subjects with asthma or rhinitis.
Positive predictive result of SPT = 50-60%; negative predictive result = 95%.
•
(1→3)-β-D-glucans are part of the carbohydrate structures in the cell walls of
molds, some bacteria, and plants; up to 60% of the dry weight of the cell wall
of fungi might be glucans.
•
Fungi contain proteases required for growth, they are also allergens that
damage and activate epithelium. PAR-1, PAR-2, PAR-3 and PAR-4 are present
on the epithelium in bronchial specimens from asthmatic and healthy subjects.
•
Chitine, chitinases and mycotoxins from fungi are potential asthma triggers.
•
Initiation of azithromycin therapy should immediately follow a different class
of antibiotic in those with purulent sputum to ‘‘clean out the airways’’ to
minimize the immediate acquisition of macrolides resistance.
•
•
HETEROGENEOUS TELOMERE DEFECTS IN PATIENTS WITH SEVERE FORMS OF DC:
•
Telomere maintenance deficiency → dyskeratosis congenita (DC), a genetic
disorder characterized by accelerated aging, progressive bone marrow failure,
and cancer predisposition. Most patients die before 10 years old.
•
Hoyeraal-Hreidarsson syndrome (HH) is a severe variant of DC in which an
early onset of bone marrow failure leading to combined immunodeficiency is
associated with microcephaly, cerebellar hypoplasia, and growth retardation.
•
Conclusions: (1) Various telomere defects can lead to similar clinical features;
(2) telomere dysfunction in cells from patients with DC/HH is not always
associated with short telomeres; (3) other factors, likely involved in telomere
protection rather than in length regulation, are guilty for a subset of DC/HH.
•
Importance: the molecular diagnosis of DC/HH patients is primarily based on
telomere length, which therefore misses patients with telomere dysfunction.
•
Telomeres are the ends of linear chromosomes. DNA replication machinery
can’t fully replicate the tip of the chromosome → progressive loss of telomeric
sequence on cell divisions. Telomerase, a ribonucleoprotein complex including
telomerase reverse transcriptase (TERT), telomerase RNA component (TERC),
Dyskerin, NOP10, and NHP2, adds telomeric sequences. However, the
expression of TERT, the catalytic subunit of telomerase, is restricted to germ
cells, stem cells, and some activated cells. Consequently, after many divisions,
somatic cells harbor short telomeres leading to cell-cycle arrest, a
phenomenon known as replicative senescence.
•
Telomeres exhibit a unique structure consisting of a telomeric loop. This
structure, maintained by a specific telomeric complex called the shelterin,
impedes the telomere from being recognized and processed as DNA-double
strand breaks. Telomeric repeat binding factor 1 (TRF1), TRF2, RAP1,
protection of telomeres protein 1 (POT1), TPP1, and TRF1-interacting protein 2
(TIN2) are the 6 known subunits of the shelterin complex. They are dedicated
to protecting chromosome ends from degradation, fusion, or both, as well as
regulating the recruitment and activity of the telomerase complex.
•
Mutations in the telomerase factors TERT, TERC, Dyskerin, TCAB1, NOP10,
NHP2, and the shelterin TIN2 were reported in patients with DC/HH, linking
impaired telomere maintenance to the disease. However, the molecular cause
of about 50% of the cases of DC/HH remains undetermined.
HETEROZYGOUS STAT3 MUTATIONS IN HYPER-IGE SYNDROME RESULT IN ALTERED BCELL MATURATION:
•
Based on CD38 and CD24 expression, CD19+ B cells were separated into
immature (CD38hiCD24hi), mature (CD38intCD24low), and memory
(CD38lowCD24hi) B cells. Alternatively, memory B cells were identified as
CD19+CD27+ cells and divided into IgG+, IgA+ switched, and IgG-IgAunswitched memory B cells.
•
•
Our data strengthen a recent report demonstrating reduced memory B cells,
both switched and unswitched, in patients with HIES. This defect, particularly
the lack of IgA+ memory B cells, might contribute to the chronic recurrent
upper and lower respiratory tract rather than systemic infections
characteristically observed in patients with STAT3-HIES.
•
Because the number of circulating B cells in patients with STAT3-HIES is
normal, the observation of increased plasma BAFF levels and parallel reduction
in BAFF-R expression was unexpected. The degree of BAFF level increase might
represent a useful diagnostic marker to estimate the effect of STAT3 mutation
in an individual patient because this cannot be determined based on
genotype-phenotype correlation. Furthermore, high BAFF levels might
contribute to the pathogenesis of lymphoid malignancies observed in patients
with STAT3-HIES because increased serum BAFF levels have been associated
with the pathogenesis of B-cell lymphoma.
•
We showed altered B cell–extrinsic and intrinsic STAT3-dependent signaling
cascades, including defects in antibody responses to immunization. We
hypothesize that clinical benefit might result from IG replacement therapy.
MENDELIAN TRAITS CAUSING SUSCEPTIBILITY TO MUCOCUTANEOUS FUNGAL
INFECTIONS IN HUMAN SUBJECTS:
•
Mutations that confer susceptibility to Candida: dectin1, CARD9, APECED, GOF
STAT1, IL17F, IL17R, STAT3, DOCK8, T cell defects, neutrophil dysfunction.
•
Although the gut is the organ primarily colonized with Candida species, fungal
infections in human subjects mainly occur on mucocutaneous surfaces, such as
the skin, nails, oral cavity, and genitals.
•
IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIF (ITAM): Conserved
tyrosine-containing peptide sequences that, once phosphorylated, serve as
‘‘docking sites’’ for additional signaling molecules.
•
NLRP3 inflammasome functions to activate the potent proinflammatory
molecules IL-1, IL-18, and IL-33.
•
PERLECHE: A superficial inflammatory condition of the angles of the mouth,
often with fissuring that is caused especially by infection or avitaminosis.
•
Candida species granulomas can form in patients with localized
mucocutaneous candidiasis. Granulomas are hyperkeratotic cutaneous lesions
that form thick crusts and are infiltrated by inflammatory cells. Those patients
can have life-impairing disabilities.
•
First line of defense against Candida: skin and mucosa, including antimicrobial
peptides and local physiologic flora.
•
Second line of defense: interplay between the innate and adaptive immune
systems.
•
Recognition of mannans in the outer portion of the Candida cell wall is
mediated by TLR4, the mannose receptor, DC-SIGN and dectin-2, whereas
dectin-1 and MINCLE bind to b-glucans in the inner portion of the cell wall.
•
It appears that C-type lectin receptors, such as dectin-1 and dectin-2, DC-SIGN,
and MINCLE are the main receptors in the recognition of C albicans.
•
TLR4 is involved in protection against disseminated C albicans infection, as well
as cytokine responses to A fumigatus conidia. TLR2 recognizes C albicans but
not A fumigatus hyphae.
•
Dectin-1 needs the phagocyte synapse to deliver activating signals. TLR can be
activated by soluble antigens.
•
Dectin-1 is thought to play a pivotal role in mucosal antifungal defense in
human subjects and mice. Being a PRR, dectin-1 signaling activates innate
immune responses, such as phagocytosis and production of reactive oxygen
species and inflammatory cytokines and chemokines. Furthermore, dectin-1
signaling shapes adaptive immune responses.
•
Dectin-2 is also a PRR for A fumigatus on DCs, and it signals through FcRγ to
generate cysteinyl leukotrienes in the allergic response to the fungus.
•
CARD9 is downstream of all myeloid receptors that contain an ITAM motif or
couple to ITAM-containing molecules and recruit and activate tyrosine kinases.
•
TH17 cells’ signature cytokines are IL-17A and IL-17F. IL-17 homodimers and
heterodimers drive the transcription of innate target genes through activation
of NF-kB. The major outcome is activation and recruitment of neutrophils and
induction of antimicrobial peptides.
•
Neutrophils: The final killers. Neutrophils have 3 main mechanisms to directly
kill invading microbes: phagocytosis and activation of the oxidative burst,
degranulation, and neutrophil extracellular traps.
•
There is no definite answer to the exact contribution of dectin-1 in the
pathogenesis of CMC; especially in view of the important role that dectin-2
plays in antifungal immunity.
•
Van de Veerdonk et al reported 4 patients who had heterozygous STAT1
coiled-coil domain missense mutations. Patients presented with AD CMC,
severe oropharyngeal chronic candidiasis, and severe dermatophytosis,
together with autoimmune phenomena, such as hypothyroidism and
autoimmune hepatitis. One patient also had squamous cell carcinoma.
•
•
•
IL-17 is very important in the human immune response against C albicans and,
to a lesser extent, against S aureus in mucocutaneous areas.
•
AIRE allows for low-level expression and presentation of tissue-specific
antigens (which are normally not expressed in the thymus) in mTECs, resulting
in deletion of self-reactive thymocytes. However, some tissue-specific antigens
are expressed by mTECs independently of AIRE. Yet AIRE seems to control
tolerance induction even to those antigens. Hubert et al showed that AIRE
regulates the transfer of these antigens from mTECs to thymic DCs for indirect
presentation and induction of negative selection. There is evidence that AIRE
also influences the development of natural regulatory T cells and induction of
peripheral tolerance through expression in peripheral lymphoid tissues.
•
In patients with recurrent infections, it is very important to obtain a detailed
family history and explicitly ask for the possibility of consanguinity. In patients
with CMC and an AD trait, mutations in STAT1 are the most frequent cause for
the phenotype. In patients with a suspected AR trait, mutations in various
genes (eg, CARD9 and IL17R) might be analyzed. The patient’s history needs to
include any signs of autoimmune phenomena. The determination of TH17 cell
numbers in peripheral blood is a challenging test but might help identify
patients with an underlying genetic condition. To what extent the above
observations will be relevant for more common clinical problems, such as
female subjects with recurrent vaginal thrush, still needs to be determined.
NATURAL COURSE AND COMORBIDITIES OF ALLERGIC AND NONALLERGIC RHINITIS
IN CHILDREN:
•
Children with allergic rhinitis ↑ from 5% (age 4) to 14% (age 8); children with
nonallergic rhinitis ↓ from 8% to 6%. RINITIS ↑ CON LA EDAD DEL NIÑO.
•
Of the children with allergic rhinitis at 4 years old, 12% underwent remission at
8 years old; of the children with nonallergic rhinitis, 73% underwent remission.
RINITIS NO ALÉRGICA TIENE MEJOR PRONÓSTICO QUE RINITIS ALÉRGICA.
•
Among 4-year children without rhinitis who were sensitized to allergen, 56%
had allergic rhinitis at 8 years old. SENSIBILIZACIÓN PREDICE RINITIS ALÉRGICA.
•
Among 4- and 8-year-old children, allergic rhinitis and nonallergic rhinitis were
associated with asthma, eczema, and food hypersensitivity (mainly to foods of
plant origin, such as fruits from Rosaceae family, tree nuts and peanuts).
•
25% of 8-year-old children with allergic rhinitis had oral allergy syndrome.
THE EFFECTS OF AN H3 RECEPTOR ANTAGONIST (PF-03654746) WITH FEXOFENADINE
ON REDUCING ALLERGIC RHINITIS SYMPTOMS:
•
Second-generation H1 receptor antagonists improve symptoms of allergic
rhinitis except nasal congestion. An oral H3 receptor antagonist decreased
nasal congestion in combination with an oral H1 receptor antagonist.
•
Oral sympathomimetic agents, either alone or in combination preparations,
can lead to adverse systemic effects, such as insomnia and hypertension.
Indeed, these agents are contraindicated in patients with cardiovascular
disease, and there have been recent concerns regarding potential for abuse.
NATURE REVIEWS IMMUNOLOGY:
•
•
•
EARLY IMMUNE EVENTS IN THE INDUCTION OF ALLERGIC CONTACT DERMATITIS:
•
PRRs are engaged by chemical contact allergens. In susceptible individuals, this
elicits an inappropriate immune response → allergic contact dermatitis.
•
One of the most important categories of contact allergens is small organic
molecules that are chemically reactive (chemical sensitizers). They bind to self
proteins to generate immunogenic neo-antigens (haptenization).
•
Compounds must be <500 daltons for efficient penetration through the skin.
EFFECTOR T CELLS CROSS THE LINE:
•
The constitutively high adhesion of effector T cells on endothelial cells required
upregulation of the α4 integrin VLA4 and the β2 integrin LFA1 (but not their
high-affinity conformations) on the T cell surface, as well as the activity of
phospholipase Cγ1, which is crucial for integrin outside-in signalling.
•
Chemokine receptor (CCR2) signalling, together with LFA1 activation, was
essential for Th1 cell and effector CD8+ T cell extravasation.
•
Chemokines (CCL2) contained in vesicles beneath the apical membrane of
endothelial cells may be locally released into focal contacts made by the
leading edge of effector T cells with the plasma membrane of endothelial cells,
and this may promote transmigration. This suggests that the use of
chemokine-specific monoclonal antibodies to block the migration of effector T
cells into inflamed tissues might not be as effective as previously thought.
EXPANDING ROLES FOR CD4+ T CELLS IN IMMUNITY TO VIRUSES:
•
Following a rapid and effective antiviral response, infection is resolved and the
majority of effector CD4+ T cells die, leaving a much smaller population of
memory CD4+ T cells that persists long-term.
•
The CD4+ T cells that are generated in response to viral infection mainly have a
TH1-type phenotype and produce large amounts of IFNγ and express T-bet.
•
Most IFNγ-producing cells in the TH1/TH2 cell population co-produced IL-4 or
IL-13. IL-12 and type I IFNs were shown to drive this TH1/TH2 cell phenotype.
•
The signature TH1 cytokine, IFNγ, enhances IgG2a class switching; this explains
why IgG2a is usually the dominant isotype in IgG responses against viruses.
•
One protective mechanism mediated by TH17 cells against virus might be the
promotion of enhanced neutrophil responses at sites of infection.
•
•
Distinct TH cell subsets (TH1, TH2, TH17) may develop into TFH cells and
provide efficient help for B cells. A recent study demonstrated that such
polarized subsets can be reprogrammed to express TFH cell characteristics.
•
IL-21 production by CD4+ T cells during chronic viral infection is crucial for
maintaining functional CD8+ T cells that are able to contain the infection.
•
CD8+ T cells that have not been helped undergo enhanced TRAIL-mediated
apoptosis following antigen re-exposure.
•
CD4+ T cells downregulate the expression of PD1 on CD8+ T cells, and this can
enhance the function of pathogen-specific memory CD8+ T cells.
•
Effector CD4+ T cells have potent protective roles during viral infection that are
independent of their helper activities.
•
Effector CD4+ T cells can effective immunoregulate at sites of infection.
•
Memory CD4+ T cells ↑ early innate immune responses after viral infection;
provide quicker help to B cells, and may be to CD8+ T cells, contributing to a
faster and more robust antiviral response. Secondary effectors derived from
memory CD4+ T cell precursors may be more potent in direct antiviral activity
than primary effectors derived from naive CD4+ T cells.
HOW DO PLANTS ACHIEVE IMMUNITY?
•
•
•
Plants lack specialized mobile immune cells but can launch effective immunity.
IL-15 PROVIDES BREATHING SPACE FOR MEMORY:
•
Memory CD8+ T cells have greater mitochondrial spare respiratory capacity
(SRC) than naive or effector T cells. SRC: the energy-producing capability that a
cell keeps in reserve for times of stress or extra work. The high SRC increases
bioenergetic stability and promotes long-term survival in the host.
•
IL-2 and IL-15 are important for development of effector and memory CD8+ T
cells, respectively. IL-15 promote mitochondrial biogenesis in memory CD8+ T
cells → more mitochondria → increased SRC → more longevity and faster
response during re-infection.
IMMUNOMODULATORY FUNCTIONS OF TYPE I INTERFERONS:
•
Viral interference: The antagonistic or inhibitory effect induced by one virus or
its components on the propagation of another virus.
•
IFNα and IFNβ, collectively known as type I IFNs, are the major effector
cytokines of the host immune response against viral infections. They can be
produced by almost any cell type.
•
•
•
•
•
Type I IFN family: 16 members (12 IFNα subtypes, IFNβ, IFNε, IFNκ and IFNω).
Type II IFN family: IFNγ, which also exhibits antiviral activities. Type III IFN
family: IFNλ1 (also known as IL-29), IFNλ2 (also known as IL-28A) and IFNλ3
(also known as IL-28B).
•
IFN-stimulated genes (ISGs). These genes contain promoters that are
responsive to IFN signalling, and they are responsible for the antiviral and
immunomodulatory properties of IFNs. Over 400 such genes have been
identified by microarray analyses.
•
STAT3 can be antiinflammatory (IL-10 action) or proinflammatory (IL-6 action).
This dual ability of STAT3 to differentially regulate inflammation explains some
of the controversial roles that type I IFNs have in different human conditions.
•
The main pitfall for the use of type I IFNs as an antitumour therapy is the
frequent severe side effects, which decrease the enthusiasm for the
application of type I IFNs in this clinical setting.
•
The reasons why IFNs restrain the development of some immunopathologies
while increasing the severity of others are still largely unknown.
INTERFERING WITH BRAIN INFLAMMATION:
•
Stimulation of RIG-I and MDA5 in peripheral DCs → type I IFN response →
engagement of IFNAR on DCs → inhibition of pathogenic TH1 and TH17 cells.
•
IFNβ is a 1st line therapy for patients with relapsing– remitting MS. Stimulating
endogenous production of type I IFNs could bypass formation of neutralizing
antibodies to exogenous IFNβ, an issue that limits clinical efficacy.
LINKING LYSOSOME FUNCTION TO MACROPHAGE HOMEOSTASIS:
•
Equilibrative nucleoside transporter 3 (ENT-3) deficiency → nucleoside
accumulation in lysosomes → lysosomal alkalization and dysfunction → delay
in degradation of apoptotic cells and live bacteria, delay in degradation of
colony-stimulating factor 1 (CSF1)–CSF1 receptor complex → persistent
CSF1-mediated signalling → increase in macrophage proliferation→
histiocytosis, splenomegaly.
•
These findings suggest a link between lysosomal storage disease and
macrophage histiocytosis.
LOSE TRAF1, LOSE CONTROL:
•
HIV infection → loss of expression of the signalling adaptor TNFR-associated
factor 1 (TRAF1) from virus-specific CD8+ T cells → decreased virus control.
•
TGFβ and IL-7 upregulated TRAF1 protein expression.
MULTIFUNCTIONAL GUT IGA+ PLASMA CELLS:
•
•
•
A subset of gut IgA+ plasma cells produce polyreactive IgA, TNF and iNOS,
maintaining intestinal microbiota and favoring immunity against pathogens.
•
The microbiota was necessary for the expression of iNOS by IgA+ cells.
NEUTROPHILS ZONE IN TO HELP B CELLS:
•
Helper neutrophils: (1) inhibited proliferation of activated CD4+ T cells, which
might promote T cell-independent antibody production; (2) induced
upregulation of AID expression in marginal zone B cells and promoted CSR,
SHM and plasma cell differentiation; (3) expressed higher levels of BAFF,
APRIL, CD40L, IL-21 and B cell chemoattractants CXCL12 and CXCL13.
•
Patients with neutrophil defects had: (1) normal numbers of total circulating B
cells but ↓ marginal zone B cells; (2) normal antibody response to T celldependent antigens (tetanus or diphtheria toxins) but ↓ antibody response to
T cell-independent antigens (LPS, lipoteichoic acid and peptidoglycan).
•
Neutrophils colonize the marginal zone of the spleen and support T cellindependent antibody responses by activating marginal zone B cells.
Neutrophils interact with marginal zone B cells to support innate-like antibody
responses, important for protection against systemic infections.
PHAGOCYTES COME BACK EVEN STRONGER:
•
•
PROTECTIVE ROLE OF INNATE-LIKE B CELLS IN SEPSIS:
•
•
Memory immune response: CD8+ memory cells → CCL3 → ‘licensing’ of
monocytes and neutrophils to kill better intracellular pathogens (higher levels
of ROS, ↑ phagosomal pH, ↑ autophagy respect to primary response).
Systemic infection → GM-CSF-producing B cells accumulate in the spleen →
bacterial clearance by ↑ neutrophil phagocytic functions. Most cells were
IgM+ B cells, developing from innate-like B-1 cells.
THE TFH-LIKE TRANSITION OF TH1 CELLS:
•
TFH cells, which support germinal centre B cell responses, can be induced by
IL-6 and IL-21 acting via STAT3, and these cells have been defined as a unique
lineage based on the expression of BCL-6 and IL-21.
•
TH1 cells are induced by IL-12 and IFNγ acting via STAT4 and STAT1,
respectively, and they express T-bet and IFNγ. Early during their development
TH1 cells pass through a transient TH1–TFH cell stage.
•
IFNγ was shown to antagonize IL-21 expression at later time points, even
though it was a positive regulator of IL-21 at early time points.
•
IL-12-activated STAT4 induced the expression of Il21, Bcl6 and Tbx21 (which
encodes T-bet), but T-bet repressed the expression of Bcl6. This suggests that,
as differentiation progresses under TH1 cell-polarizing conditions, T-bet
suppresses the TFH cell phenotype. Conversely, overexpression of BCL-6
suppressed both IFNγ and T-bet expression in TH1 cells.
•
TRANSCRIPTIONAL PROGRAMMING OF THE DENDRITIC CELL NETWORK:
•
The four major categories of DCs are conventional DCs (resident and
migratory), which predominate in the steady state; Langerhans cells; pDCs;
and monocyte-derived DCs, which are induced in response to inflammation.
•
CD8α+ DCs are noted for their capacity to cross-present antigens and for their
major role in priming cytotoxic CD8+ T cell responses. CD4+ DCs and CD4–
CD8α– DCs can also present MHC class I-restricted antigens in some settings,
but appear to be more efficient at presenting MHC class II-associated antigens
to CD4+ T cells.
•
Lymphoid tissue-resident DCs develop from precursor DCs found in lymphoid
tissues themselves. Without infection, they exist in an immature state (high
endocytic capacity and low MHC class II expression). They are ideally placed to
sense antigens or pathogens that are transported in the blood.
•
All DCs, except Langerhans cells, are derived from bone marrow-resident HSCs.
Langerhans cells are derived from a local LY6C+ myelomonocytic precursor cell
population in the skin. This precursor population originates from macrophages
that are present early in embryonic development and that undergo a
proliferative burst in the epidermis in the first few days after birth.
•
pDCs are quiescent cells broadly distributed in the body. They can rapidly
produce large amounts of type I IFNs, most evident during viral infection.
•
Monocyte-derived DCs are a crucial reservoir of professional APCs that are
recruited into immune responses to certain microorganisms and potentially
have an emergency back-up role in cases of acute inflammation.
•
The differentiation of DCs from HSCs relies on the activity of FMS-related
tyrosine kinase 3 ligand (FLT3L), M-CSF and GM-CSF. FLT3L - FLT3 is the bestcharacterized growth factor–receptor axis for DCs. In all cell lineages except
the DC lineage, FLT3 is downregulated following differentiation and, at least in
the case of B cells, this repression of FLT3 is essential for further development.
•
GM-CSF has a greater role in the production of monocyte-derived DCs than in
the generation of other DC subsets.
•
M-CSF is the major cytokine for production of monocytes and macrophages.
•
Mice lacking M-CSF have normal numbers of Langerhans cells, a quandary that
was resolved by the identification of IL-34 as a second ligand for M-CSFR.
•
The separation of pDC and conventional DC lineages represents the first major
division in the DC pathway and requires the concerted action of E proteins and
the PU.1–IRF8 complex.
•
NFAT (Nuclear factor of activated T cells). A family of transcription factors that
are regulated by calcium signalling and expressed by a variety of immune cells.
•
AP1 (Activator protein 1). A transcription factor composed of proteins from to
the FOS, JUN and JUN-dimerization protein families. AP1 controls various
cellular processes, including differentiation, proliferation and apoptosis.
•
Cross-priming. A mechanism by which CD8+ T cells are activated by the
presentation of an antigen that was not synthesized by the APC itself.
•
Lymphoid tissue-inducer cells. A cell type that is present in developing lymph
nodes, Peyer’s patches and nasopharynx-associated lymphoid tissue (NALT).
LTi cells are required for the development of these lymphoid organs.
•
E protein. The E proteins (including E12, E47, HEB and E2-2) have emerged as
key regulators of the immune system. They are a family of basic helix-loophelix factors that work together with their antagonists, the ID proteins (ID1–
ID4), to regulate lymphocyte development.
•
IRF8 is highly expressed in CDPs, pDCs and conventional DCs, particularly the
CD8α+ and CD103+ DC subsets. IRF8-deficient mice lack many DC subsets,
including Langerhans cells. IRF8 controls functional features of DCs, such as
expression of TLR9 and IFNα by pDCs and production of IL-12 by CD8α+ DCs.