chronic urticaria. mast cell before: resting cell after: activated cell
TRANSCRIPT
Chronic Urticaria
Mast CellMast Cell
Before: Resting CellBefore: Resting Cell After: Activated CellAfter: Activated Cell
Allergen-IgE dependent Mast Cell Activation:Allergen-IgE dependent Mast Cell Activation: Signal Transduction Signal Transduction PathwaysPathways
Mast Cell Activation
Mast cell mediators
CU-histology
Lesional T cells in CU …the presence of activated T cells in the dermis may play a role in the pathogenesis of the skin lesions in CU.
Mekori YA et al. J Allergy Clin Immunol 72:681, 1983
…Our results suggest that the infiltrate resembles that observed in cellular immune reactions (although no antigen has been identified) and that interaction of T-lymphocytes and/or monocytes with mast cells to cause mediator release appears likely.
Elias J et al. J Allergy Clin Immunol 78:914, 1986
Activated T CellsActivated T Cells
J.J. Immunol 160:4026, 1998Immunol 160:4026, 1998J. Leukoc. BiolJ. Leukoc. Biol. . 63:33763:337,, 19981998
contactcontact Activation of Mast CellsActivation of Mast CellsDegranulation; Release of TNF-Degranulation; Release of TNF-
A Novel Mast Cell Activation Pathway:A Novel Mast Cell Activation Pathway:
00
1010
2020
3030
4040
BMMCBMMCalonealone
+ N.T.+ N.T. + IgG+ IgG + anti CD3+ anti CD3
His
tam
ine
Rel
ease
(%
of
tota
l)H
ista
min
e R
elea
se (
% o
f to
tal)
NormalNormalTranswellTranswell
+ 2B4 cells incubated on wells coated with:+ 2B4 cells incubated on wells coated with:
Induction of Degranulation is Inhibited by SeparationInduction of Degranulation is Inhibited by Separationof T Cells and Mast Cellsof T Cells and Mast Cells
Increased p21Ras Expression in PBMC of Patients
with CU
Confino et al. JACI Jan. 200l
Anti FcRI/IgE
0.05 ml autologous serum i.d. to uninvolved skin
+result = wheal 1.5mm>control (NaCl) at 30 min. ( 80% sens. /spec.)
FcRI
Positive Autologous Serum Test
CU sera-inducing degranulation
Effect of C5 on Degranulation
Points in Favour of Pathogenic Ab in CIU
• Passive transfer of autologous ST to healthy volunteers
(Adv Dermatol 15:311, 1999)
• Correlation of functional autoAb plasma levels with severity (Lancet 339:1078, 1992)
• Disease remission following removal (plasmapheresis) or suppression (IVIG) of the antibody (BJD 138:101,1998)
Prevalence of Autoantibodies in 78 Patients with CU Sabroe RA & Greaves MW BJD 154:813, 2006
(IgG1 , IgG3)
(IgG2, IgG4)
Thyroid Autoimmunity in Chronic Urticaria
27% of patients with CU have anti thyroid Ab. 19% have abnormal thyroid functionKaplan AP N Eng J Med 346:175, 2002
24% of patients with CIU had at least one type of anti thyroid Ab. 42% of the seropositive pt. had thyroid disease or altered TSH levels. Zauli D et al Allergy Asthma Proc 22:93, 2001 10 euthyroid patients with CU. 7/10 had anti thyroid Ab. All seven reported resolution of symptoms within 4 wk of thyroxine treatment. Other 3 patients did not respond. 5 patients had a recurrence of symptoms after treatment was stopped, which resolved after treatment was restarted.TSH decreased in all pt. With a clinical response.Rumbyrt JS et al J Allergy Clin Immunol 96:901, 1996
Clinical and laboratory parameters in predicting chronic urticaria duration: a prospective study of 139 patients
139 patients with CU70% > 1 year14% >5 years
CU duration is associated with clinical parameters such as:
•severity and angioedema
•autologous serum test and anti-thyroid antibodies
Toubi E et al Allergy 59:869, 2004
Potential Causes of Chronic Urticaria
• Occupational/Contactants• Medications• Foods/additives/CAM products (Echinacea; Ann Allergy 88:42, 2002)
• Physical• Infections (viral; focal)• Autoimmune (SLE; MCTD; thyroiditis; FcRI)• Vasculitis (less than 1%)• Hormonal dysfunctiuon (thyroid; pregnancy; menstrual)• Malignancy• Mastocytosis
Dermographism
Cold Urticaria
Delayed Pressure Urticaria
Cholinergic Urticaria
Eleven of 17 patients with cholinergic urticaria showed positive reactions in skin tests with their own diluted sweat .
Eleven of 17 patients with cholinergic urticaria showed positive reactions in skin tests with their own diluted sweat. Substantial amounts of sweat-induced histamine release from autologous basophils were observed in 10 of 17 patients. Eight of 15 patients with cholinergic urticaria showed positive reactions in the autologous serum skin tests. All 6 patients who developed satellite wheals after the acetylcholine test showed hypersensitivity to sweat. Further, patients whose eruptions were coincident with hair follicles showed positive responses to the skin test with autologous serum, whereas patients whose eruptions were not coincident with hair follicles did not.
Fukunaga A et al J allergy Clin Immunol 116: 397, 2005
CU-Exacerbating Factors
Viral Infection
NSAID
Alcohol
Overheating
Treatment of CU
Suggestive Therapeutic approach for CU Patients with AutoAb +
BJD 154:813, 2006
CU-Experimental Therapies
• Cyclosporine (2.5-4 mg/kg); Tacrolimus (70% response rate)
• Plasmapheresis (pts. with FcRI Ab)
• IVIG
• Levothyroxine (for pts. with thyroid Ab)• Anti IgE mAb (effect on FcRI expression)