*3.4. Pathogenesis and Immunological Implications*

The exact mechanism that triggers HS is not fully understood. Feasibly, the formation of immune complexes is strongly suspected (Gell and Coombs type III reaction) and the cellmediated reaction (Gell and Coombs type IV reaction) may contribute to the development of this challenging disease.

Some cases showed positive skin tests [3,7], high serum total IgE levels [7], high milk-specific IgE antibodies [13,14] or circulating immune complexes [3]. A significant increase of histamine and ECP in BAL several hours after a milk OFC was reported [10]. In one case report, deposits of immunoglobulins, complement, fibrin and milk protein antigens diffusely scattered were described on immunofluorescence studies of lung tissue biopsies [2]. It is probable that a cause concurring to HS is the aspiration of milk, in particular among patients with an uncoordinated swallowing mechanism, tracheal/esophageal anomaly or gastroesophageal reflux. However, in the paper of Boat et al., this condition was ruled out [7]. Concerning the data on delayed immunity, in some cases a delayed skin test response to intradermal test [3,7] or a lymphocyte response [8] was reported. Other authors postulated that milk antigens might trigger an immune complex reaction resulting in multiorgan abnormalities, such as pulmonary, gastrointestinal and renal ones. In fact, pulmonary and gastrointestinal signs and symptoms were frequently associated [11] and granular immuno-deposits have been demonstrated along the glomerular basement membrane in a child with crescentic glomerulonephritis and PH [13].

Most studies, mainly the oldest ones, characteristically found high titers of precipitins (likely immunoglobulins of class G) against bovine milk proteins in the patients' sera, by using the Ouchterlony double-immunodiffusion technique [4,5,7,11]. However, it is not sufficiently explicable why some children develop precipitating antibodies to ingested protein and other children do not. Moreover, it is not known if these precipitins play a causative role in the disease. Children with precipitins usually have an increased incidence of recurrent respiratory tract diseases, anemia and hepatosplenomegalia. However, precipitating IgG antibodies to milk are not pathognomonic of the disease, since they have been found among around 1% of healthy children in the absence of clinical manifestations [4], and in 4% to 6% of children with chronic disorders, including celiac disease, cystic fibrosis, IgA deficiency, Down's syndrome, Wisckott–Aldrich syndrome and Hurler's syndrome [7]. Additionally, methods used for detecting precipitins are obsolete and reports on them are timeworn. Therefore, the role of these antibodies should be critically considered.

In other more recent reports, high values of specific IgG to milk proteins were found using an immunoenzimatic technique [14]. In one case report [15] CM IgG4 was found to be elevated. Even in these cases, the role of this specific CM IgG is not clear.
