The relevance of the IgG subclass of autoantibodies for blister induction in autoimmune bullous skin diseases Autoimmune bullous skin diseases are characterized by autoantibodies and T cells specific to structural proteins maintaining cell -- cell and cell -- matrix adhesion in the skin . Existing clinical and experimental evidence generally supports a pathogenic role of autoantibodies for blister formation . These autoantibodies belong to several IgG subclasses , which associate with different functional properties and may thus determine the pathogenic potential of IgG antibodies . In pemphigus diseases , binding of IgG to keratinocytes is sufficient to cause intraepidermal blisters without engaging innate immune effectors and IgG4 autoantibodies seem to mainly mediate acantholysis . In contrast , in most subepidermal autoimmune blistering diseases , complement activation and recruitment and activation of leukocytes by autoantibodies are required for blister induction . In these conditions , tissue damage is thought to be mainly mediated by IgG1 , but not IgG4 autoantibodies . This review summarizes the current knowledge on the pathogenic relevance of the IgG subclass of autoantibodies for blister formation . Characterization of the pathogenically relevant subclass -LRB- es -RRB- of autoantibodies not only provides mechanistic insights , but should greatly facilitate the development of improved therapeutic modalities of autoimmune blistering diseases . Introduction Autoimmune blistering diseases are associated with an autoimmune response directed to structural proteins mediating cell -- cell and cell -- matrix adhesion in the skin -LSB- 62 , 66 -RSB- . Both autoantibodies and autoreactive T cells have been found in patients with these organ-specific autoimmune diseases . However , blister induction is mainly mediated by autoantibodies . Autoimmune blistering diseases are classified based on the ultrastructural site of deposition of immunoreactants and on the molecular target of autoantibodies . Diseases of the pemphigus group are associated with autoantibodies to epidermal components mediating cell -- cell adhesion and are characterized by acantholytic blisters within the epidermis -LSB- 39 , 71 -RSB- . Tissue-bound and circulating autoantibodies to the dermal -- epidermal junction are characteristic immunopathological features of subepidermal autoimmune bullous diseases -LSB- 62 , 85 -RSB- . Target antigens of autoantibodies have been identified for the majority of autoimmune blistering diseases . In most of these diseases , the pathogenicity of autoantibodies is supported by clinical observations and extensive experimental evidence -LSB- 62 -RSB- . Antibodies are effector molecules of the adaptive immune system secreted by plasmablasts and long-lived plasma cells . Antibody responses are physiologically mounted following an infection or vaccination and protect against various pathogens . Occasionally , in the setting of an autoimmune disease , antibodies to autologous structures may develop and cause different forms of tissue damage . The immunopathology induced by autoantibodies , similar to the immunity mediated by antibodies to pathogens , relies on several mechanisms of action of antibodies , including direct mechanisms , which are mediated by the antibody 's variable regions -LRB- e.g. , by steric hindrance and signal transduction -RRB- , and indirect mechanisms , which are triggered by the constant regions of antibodies . For the latter , -LRB- auto -RRB- antibodies typically interact through their Fc portions with other factors of the innate immune system , including the complement system and inflammatory cells -LSB- 62 -RSB- . Antibodies of the IgG isotype predominate in the systemic immune response , as reflected in serum immunoglobulin concentration , and activate a wide range of effector functions . Four subclasses of IgG are defined , originally from the antigenic uniqueness of their heavy chains , which are products of distinct genes -LSB- 20 , 27 , 77 -RSB- . The subclasses are designated as IgG1 , IgG2 , IgG3 and IgG4 in order of their serum concentration ∼ 60 , 25 , 10 and 5 % , respectively . Although the heavy chains show > 95 % sequence homology , each IgG subclass expresses a unique profile of effector activities -LSB- 35 , 56 , 59 , 76 , 80 , 82 -RSB- . Protein antigens characteristically provoke IgG1 and IgG3 responses and these isotypes are able to activate all types of Fc receptors and the C1 component of complement . The IgG4 subclass may be characteristic of chronic antigen stimulation , as in autoimmune disease ; it has restricted Fc receptor activating abilities and does not activate C1q . The IgG2 subclass often predominates in responses to carbohydrate antigens ; it has restricted Fc receptor and C1 activating abilities -LSB- 35 , 56 , 80 , 82 -RSB- . The pathogenic potential unfolded by autoantibodies is determined not only by their specificity and affinity , but also by their isotype . Autoantibodies against cutaneous proteins in autoimmune blistering diseases belong to different IgG subclasses . This paper summarizes the current knowledge on the relevance of IgG subclasses for tissue injury in autoimmune bullous diseases . Pemphigus diseases Pemphigus designates a group of life-threatening-autoimmune blistering diseases characterized by intraepithelial blister formation caused by loss of cell -- cell adhesion -LSB- 39 , 54 , 71 -RSB- . IgG autoantibodies in patients with pemphigus seem to mediate their pathogenic functions independently of their Fc portions -LSB- 62 -RSB- . Patients ' IgG autoantibodies are pathogenic in C5-deficient mice and F -LRB- ab ' -RRB- 2 , Fab , and scFv fragments of autoantibodies induce acantholysis by passive transfer in wild type mice showing that complement activation or other Fc-mediated effects are not required for pathogenicity -LSB- 4 , 21 , 45 , 55 -RSB- . Numerous studies clearly demonstrated that tissue bound and circulating autoantibodies in pemphigus patients mainly belong to the IgG1 and IgG4 subclasses -LSB- 2 , 5 , 8 , 9 , 16 -- 18 , 23 , 28 , 36 , 38 , 40 , 49 , 61 , 79 -RSB- . The IgG subclass distribution of autoantibodies in a representative pemphigus patient is shown in Fig. 1 . While it is generally agreed upon the subclass distribution of IgG autoantibodies , the relevance of autoantibodies of different IgG isotypes for acantholytic blistering in pemphigus is still a matter of debate . IgG4 autoantibodies , known to have poor complement - and leucocyte-activating properties , predominate in pemphigus vulgaris and foliaceus . While several studies suggest a pathogenic role of IgG4 in pemphigus , the capacity of IgG1 autoantibodies to induce acantholysis has not yet been ruled out . In patients with active pemphigus vulgaris , IgG4 autoantibodies against desmogleins were found to predominate -LSB- 5 , 17 , 23 , 40 -RSB- . The transplacental transfer of these autoantibodies in mothers with pemphigus induces acantholytic skin disease in neonates -LSB- 52 -RSB- . In endemic pemphigus foliaceus the early antibody response in normal subjects living in the endemic area and in patients before the onset of clinical disease is mainly IgG1 . Acquisition of an IgG4 response seems to be a key step in the development of clinical disease -LSB- 78 -RSB- . Clinical and experimental data suggests that IgG1 differ from IgG4 autoantibodies in terms of both their epitope specificity and pathogenic potential -LSB- 9 , 42 -RSB- . A monoclonal IgG4 antibody against desmoglein 3 generated from a patient with active pemphigus vulgaris induces acantholysis in cultured skin and when injected in neonatal mice -LSB- 86 -RSB- . The fact that IgG4 antibodies purified from patients with fogo selvagem , an endemic form of pemphigus foliaceus , are pathogenic in mice further supports the notion that IgG4 is pathogenic and complement activation is not required for blister formation -LSB- 57 -RSB- , but does not exclude a pathogenic potential of IgG autoantibodies belonging to other subclasses . Indeed , in several pemphigus foliaceus patients , only IgG1 autoantibodies were found that caused intraepidermal blisters by passive transfer into neonatal mice -LSB- 29 -RSB- . This observation clearly shows that autoantibodies of different subclasses may display blister-inducing activity . In addition , in paraneoplastic pemphigus , autoantibodies against desmoglein 3 mainly belong to the IgG1 and IgG2 subclasses suggesting that the IgG subclass per se is not a direct determinant of the antibodies ' pathogenic potential in pemphigus -LSB- 24 -RSB- . Fig. 1IgG subclass distribution of circulating pemphigus autoantibodies . A 1:10 dilution of serum from a patient with pemphigus foliaceus was incubated with 6 μm-thick cryostat sections of normal human skin for 30 min at room temperature . Bound antibodies , visualized using an FITC-labeled antibody specific to human IgG , were of a IgG1 and d IgG4 subclasses . In contrast , no binding of b IgG2 and c IgG3 autoantibodies was evidenced Experimental evidence using a murine model of pemphigus vulgaris shows that , similar to human pemphigus , the autoimmune response in mice is biased toward non-complement fixing autoantibodies . In this model , in immunodeficient mice infused with splenocytes from desmoglein-deficient mice immunized against this antigen , IgG autoantibodies are produced by homeostatically expanded antigen-specific B cells under T cell control and mice develop a phenotype reminiscent of pemphigus vulgaris . These IgG autoantibodies predominantly belong to the IgG1 subclass , which is a non-complement fixing antibody in the mouse -LSB- 3 , 50 -RSB- . These results demonstrate that non-complement-fixing autoantibodies can induce acantholysis and suggest a similar mechanism in patients , but they do not exclude a pathogenic potential of patients ' IgG1 autoantibodies in pemphigus . In conclusion , in pemphigus diseases the autoantibodies mainly belong to the IgG4 and IgG1 subclasses . Extensive experimental evidence demonstrates the blister-inducing potential of IgG4 autoantibodies . The pathogenic activity of autoantibodies of other subclasses seems likely , but needs further investigation . Subepidermal autoimmune blistering diseases Bullous pemphigoid and pemphigoid gestationis Bullous pemphigoid is an autoimmune blistering disease characterized by subepidermal blisters and associated with linear deposits of C3 and IgG at the epidermal basement membrane zone . Autoantibodies in bullous pemphigoid are directed against two hemidesmosomal antigens , BP230 and BP180/type XVII collagen -LSB- 87 -RSB- . Pemphigoid gestationis , also referred to as herpes gestationis , is a subepidermal blistering disease associated with pregnancy and characterized by linear deposition of C3 and , to a lesser extent of IgG at the dermal -- epidermal junction , as detected by immunofluorescence microscopy -LSB- 62 , 66 -RSB- . The autoimmune response in bullous pemphigoid and pemphigoid gestationis is mainly directed against epitopes clustered within the immunodominant 16th non-collagenous -LRB- NC16 -RRB- A region of type XVII collagen -LSB- 48 , 65 , 88 -RSB- . Experimental evidence generally supports the pathogenic role of autoantibodies against type XVII collagen for blister formation . Data from passive transfer animal models strongly suggest that antibodies to type XVII collagen are directly involved in the pathogenesis of bullous pemphigoid -LSB- 44 , 84 -RSB- . In addition , in an ex vivo model utilizing cryosections of human skin , it has been demonstrated that binding of autoantibodies to the immunodominant NC16A domain of type XVII collagen , is the first critical step in subepidermal blister formation -LSB- 31 , 64 -RSB- . Analysis of the subclass distribution of IgG autoantibodies in the skin of patients with bullous pemphigoid by immunofluorescence microscopy , revealed IgG4 as being the predominant subclass of autoantibodies in bullous pemphigoid , followed by IgG1 autoantibodies , while IgG2 and IgG3 autoantibodies were found only occasionally -LSB- 1 , 10 -- 12 , 22 , 61 , 83 -RSB- . In addition , serum autoantibodies binding to the dermal -- epidermal junction by immunofluorescence microscopy also mainly belong to the IgG4 and IgG1 subclasses -LSB- 10 , 11 , 61 , 83 -RSB- . Subsequent molecular analysis of IgG autoantibodies by immunoblotting and ELISA generally confirmed the predominance of IgG1 and IgG4 autoantibodies reactive with type XVII collagen and BP230 -LRB- Fig. 2 -RRB- -LSB- 6 , 19 , 32 , 41 , 69 -RSB- . Fig. 2IgG1 and IgG4 autoantibodies mainly target type XVII collagen in bullous pemphigoid . Immunoblot analysis of serum from a bullous pemphigoid patient with recombinant type XVII collagen revealed that reactivity against its immunodominant domain consists mainly of IgG1 -LRB- lane 1 -RRB- and IgG4 -LRB- lane 4 -RRB- , and less IgG2 -LRB- lane 2 -RRB- and IgG3 -LRB- lane 3 -RRB- autoantibodies In contrast to bullous pemphigoid , in pemphigoid gestationis tissue-bound and circulating autoantibodies seem to mainly belong to the IgG1 and IgG3 subclasses -LSB- 14 , 37 -RSB- . However , a recent study challenged these reports revealing IgG4 as the predominant IgG subclass of tissue-bound autoantibodies in pemphigoid gestationis patients -LSB- 53 -RSB- , a pattern similar to the one found in bullous pemphigoid . Further studies should solve this contradiction . Data from several studies in patients suggested a pathogenic role of IgG1 autoantibodies for blister formation -LRB- briefly reviewed in -LSB- 43 -RSB- -RRB- . In a recent study , ELISA analysis showed that autoantibodies against the N-terminus of the extracellular domain of type XVII collagen predominantly belong to the IgG1 subclass . More importantly , a NC16A-specific IgG1 response was predominant in the acute phase of bullous pemphigoid , while IgG4 was predominantly detected in bullous pemphigoid patients in remission -LSB- 32 -RSB- . Using immunoaffinity purified IgG subclasses , it has been shown that IgG1 , but not IgG4 autoantibodies from bullous pemphigoid patients activate the complement system in vitro -LRB- Fig. 3 -RRB- -LSB- 46 , 72 -RSB- . This observation is in line with the currently accepted view that IgG4 is unable to activate the classical pathway of complement . However , until recently it was unclear which IgG subclass is actually pathogenic in bullous pemphigoid . Using the ex vivo cryosection model , we demonstrated that , in addition to IgG1 , IgG4 autoantibodies are also able to activate leukocytes and to induce leukocyte-dependent tissue damage -LRB- Fig. 4 -RRB- -LSB- 46 -RSB- . Our results are in line with recent studies demonstrating that both polyclonal human IgG1 and IgG4 from patients with Wegener 's granulomatosis and chronic urticaria can activate leukocytes -LSB- 33 , 70 -RSB- . Although the pathogenic potential of IgG4 autoantibodies was significantly lower compared to IgG1 , IgG4 autoantibodies , which generally predominate , may activate the inflammatory cells already recruited into the upper dermis by complement-fixing IgG1 autoantibodies and thus amplify the recruitment of additional leukocytes and the extent of blister formation . Therefore , when associated with IgG1 and/or IgG3 autoantibodies , IgG4 may significantly contribute to the pathology induced by autoantibodies in antibody-induced granulocyte-mediated autoimmune blistering diseases -LSB- 46 -RSB- . Fig. 3IgG4 autoantibodies , in contrast to IgG1 , do not fix complement to the dermal -- epidermal junction in bullous pemphigoid . Cryosections of normal human skin were incubated with serum and immunoaffinity purified IgG1 and IgG4 antibody preparations from a bullous pemphigoid patient and , subsequently , treated with normal human serum as a source of complement . Both a serum and b purified IgG1 autoantibodies fixed complement C3 at the dermal -- epidermal junction in a linear fashion . c In contrast , incubation of cryosections with IgG4 specific for the dermal -- epidermal junction does not result in C3 deposition -LRB- all magnifications , × 200 -RRB- Fig. 4IgG4 autoantibodies from bullous pemphigoid patients induce dermal -- epidermal separation in sections of human skin . Dermal -- epidermal separation in sections of normal human skin is induced by a IgG1 and b IgG4 autoantibodies from a bullous pemphigoid patient . c IgG antibodies from a healthy control -LRB- NHS -RRB- do not induce subepidermal splits -LRB- all magnifications , × 200 -RRB- Several reports suggested that binding of bullous pemphigoid antibodies to keratinocytes triggers a signal transduction -LSB- 58 , 73 -- 75 -RSB- . Bullous pemphigoid autoantibodies trigger a signal-transducing event that leads to expression and secretion of interleukin-6 and interleukin-8 from human cultured keratinocytes -LSB- 58 -RSB- . A series of studies from another group demonstrated that IgG1 autoantibodies from bullous pemphigoid patients and rabbit IgG against type XVII collagen induces Ca2 + release from intracellular storage sites -LSB- 73 -- 75 -RSB- . Interestingly , complement activation by these IgG1 autoantibodies did not result in lysis of keratinocytes -LSB- 73 -RSB- . While the relevance of these findings is not yet fully understood , IgG2 and IgG4 patients ' autoantibodies were found to inhibit the transient increase of intracellular Ca2 + induced by bullous pemphigoid IgG1 antibody -LSB- 74 -RSB- . Mucous membrane pemphigoid Mucous membrane pemphigoid is a heterogeneous disease with regard to the clinical phenotype and the target antigens . Different target antigens have been identified in mucous membrane pemphigoid , including BP180 , laminins 5 -LRB- epiligrin -RRB- and 6 , β4 integrin -LSB- 62 , 66 -RSB- . In general , autoantibodies in mucous membrane pemphigoid mainly belong to the IgG4 and IgG1 subclasses -LSB- 7 , 34 -RSB- . Interestingly , in anti-epiligrin cicatricial pemphigoid , autoantibodies against laminin 5 almost exclusively belong to the IgG4 subclass -LSB- 34 -RSB- . Consistent with these findings , sera from patients with anti-laminin 5 IgG autoantibodies do not fix C3 to the epidermal basement membranes and do not induce leukocyte-dependent dermal -- epidermal separation in vitro -LSB- 34 , 60 -RSB- . These data suggest that complement activation does not play a major role in this disease and subepidermal blisters in these patients may develop via a direct effect of anti-laminin 5 IgG itself -LSB- 34 , 60 -RSB- . Diseases associated with autoimmunity against type VII collagen Epidermolysis bullosa acquisita is a chronic subepidermal blistering disease characterized by circulating and tissue-bound antibodies targeting the non-collagenous domain 1 -LRB- NC1 -RRB- of type VII collagen . The pathogenic relevance of antibodies against type VII collagen is supported by compelling evidence : -LRB- 1 -RRB- autoantibodies from patients with epidermolysis bullosa acquisita were shown to recruit and activate leukocytes ex vivo resulting in dermal -- epidermal separation in cryosections of human skin -LSB- 60 , 63 -RSB- , -LRB- 2 -RRB- antibodies against type VII collagen induce subepidermal blisters when passively transferred into mice -LSB- 67 , 81 -RSB- , -LRB- 3 -RRB- immunization with recombinant autologous type VII collagen induces an autoimmune response to this protein resulting in a blistering phenotype closely resembling human epidermolysis bullosa acquisita -LSB- 68 -RSB- . Tissue-bound and circulating antibodies in epidermolysis bullosa acquisita patients mainly belong to the IgG1 and IgG4 subclasses -LSB- 7 , 15 , 26 , 47 -RSB- . A similar distribution of IgG subclasses of autoantibodies is found also in SJL mice immunized against murine type VII collagen -LSB- 68 -RSB- . In these mice , while both non-complement-fixing IgG1 and complement-fixing IgG2a and IgG2b autoantibodies are produced after immunization , IgG2a/b autoantibodies seem to induce blistering -LSB- 68 -RSB- . Systemic lupus erythematosus and inflammatory bowel diseases may be also associated with autoantibodies against type VII collagen -LSB- 13 , 25 , 30 , 51 -RSB- . However , in contrast to epidermolysis bullosa acquisita , autoantibodies from patients with bullous systemic lupus erythematosus and inflammatory bowel diseases mainly belong to IgG2 and IgG3 , respectively -LSB- 30 , 51 -RSB- . The pathogenic relevance of autoantibodies against type VII collagen in inflammatory bowel diseases has not yet been addressed -LSB- 51 -RSB- . IgG autoantibodies from patients with bullous systemic lupus erythematosus were shown to induce leukocyte-dependent dermal -- epidermal separation in cryosections of human skin ex vivo -LSB- 30 -RSB- . This findings suggest that the presence of complement-fixing autoantibodies is not a strict requirement for blistering in patients . Conclusion and perspectives The polyclonal antibody response against structural skin proteins in autoimmune bullous diseases is heterogeneous , but shows a skewing in subclass distribution of autoantibodies . The strong bias toward production of IgG4 autoantibodies in these organ-specific autoimmune diseases suggests chronic antigenic stimulation . In pemphigus , IgG4 autoantibodies that dominate the autoimmune response are clearly pathogenic . However , IgG1 autoantibodies also likely possess blister-inducing potential that requires further investigation . In subepidermal autoimmune blistering diseases , the effector functions of autoantibodies are important for blistering . Thus , in bullous pemphigoid and epidermolysis bullosa acquisita , complement-fixing IgG1 autoantibodies may show a significantly higher pathogenic potential when compared with IgG4 autoantibodies . Characterization of the blister-inducing capacity of different subclasses of autoantibodies in autoimmune bullous diseases will not only provide relevant mechanistic insights , but should also greatly facilitate the development of improved therapeutic modalities of autoimmune blistering diseases . Detailed knowledge on the pathogenic IgG isotype -LRB- s -RRB- will serve as a basis for the development of IgG subclass-specific immunoapheresis , skewing autoantibody production toward non-pathogenic subclasses by immunotherapy or blocking of complement or leukocytes activation by targeting specific IgG subclasses . A promising approach is represented by interventions aimed at inhibiting the production of autoantibodies in general or skewing the production of autoantibodies toward non-pathogenic subclasses . The molecular targets of these approaches may include different cytokines -LRB- e.g. , IL-12 and IL-17 -RRB- and their activity could be modulated using inhibitory antibodies , small peptide inhibitors or peptidomimetics as well as immunization with the autoantigen together with adjuvants known to induce a Th2 immune response .

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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autoimmune bullous diseases
igg subclasses
complement


Contribution of psychoacoustics and neuroaudiology in revealing correlation of mental disorders with central auditory processing disorders Background Psychoacoustics is a fascinating developing field concerned with the evaluation of the hearing sensation as an outcome of a sound or speech stimulus . Neuroaudiology with electrophysiologic testing , records the electrical activity of the auditory pathways , extending from the 8th cranial nerve up to the cortical auditory centers as a result of external auditory stimuli . Central Auditory Processing Disorders may co-exist with mental disorders and complicate diagnosis and outcome . Background Evaluation of the central auditory nervous system -LRB- CANS -RRB- is essential in order to obtain information on its anatomical and functional integrity . Both , children and adults may suffer from central auditory processing disorders -LRB- CAPD -RRB- . This fact has been underestimated but as research in this field progresses , it shows that specific mental disorders may be the outcome of a CAPD or that CAPD can co-exist with a neurological or mental disorder -LSB- 1 -RSB- . Assessment of the CANS begun at the mid-1950s with the confirmation by Bocca and his colleagues -LSB- 2 -RSB- that CANS disorders do exist and that there are sensitive tests to reveal them . However , at that time acceptance of the new diagnostic methods by the audiologists , who were the first to be interested in this field was limited . This can be attributed to the slow acceptance of each new method before it is fully validated . Better understanding of the anatomy and physiology of the CANS was gained by advances concerning the presence and physiology of neurotransmitters and the accumulation of data on the psychoacoustic and electrophysiologic tests -LSB- 3 -RSB- . As a result audiologists started applying the new diagnostic tests more often and appreciated their contribution . Other medical specialties became aware and interested in the disorders of the CANS . These were mainly psychiatry and neurology . The assessment of the CANS is also of great value concerning neuropsychology and special education -LSB- 4-6 -RSB- . Anatomy and physiology of the CANS Clinical evaluation of central auditory function requires understanding of the anatomy and physiology of the CANS and appreciation of its complexity . The CANS extends from the anterior and posterior cochlear nuclei which are situated on the surface of the inferior cerebellar peduncle to the auditory cortex . In between important structures through which nerve fibers pass are : the trapezoid body , the lateral lemniscus , the inferior colliculus , the medial geniculate body and the acoustic radiation of the internal capsule . The auditory cortex includes the gyrus of Heschl on the upper surface of the superior temporal gyrus , the planum temporale and the Silvian fissure . It is essential to point out that nerve impulses from each ear proceed along auditory pathways on both sides of the brainstem . Both ipsilateral and contralateral pathways are important in ensuring interchange of auditory information . The contralateral pathway exhibits dominance as opposed to the ipsilateral one -LSB- 7 -RSB- . Thirty thousand afferent auditory nerve fibers with different range of frequency response are responsible for conveying auditory information to the cortex -LSB- 8 -RSB- . Many components of the stimulus are analyzed separately . There is an increasing complexity of the whole process in the auditory cortex . One should keep in mind that , understanding of the exact way of processing the auditory information at the level of the auditory cortex , is still incomplete . It is in this understanding that Phychoacoustics helps as it is the science concerned with the evaluation of the sensation of hearing as an outcome of the sound or speech stimulus . Components of central auditory processing Central auditory processing occurs prior to language comprehension -LSB- 9 -RSB- . It consists firstly of auditory discrimination , which is responsible for the ability to group sounds according to how similarly or differently they are heard . Auditory memory is the component responsible for storing and recalling auditory information . Auditory perception concerns the reception and understanding of sounds and words . It plays a significant part in reading skills , managing verbal information , communication and social relationships . Auditory-vocal association consists of the interaction between what is heard and verbal response . Auditory synthesis is responsible for combining sounds or syllables to formulate comprehensible patterns -LRB- words -RRB- and de-combining words into separate sounds . Auditory-vocal automaticity is the ability to predict how future linguistic events will be heard by utilizing past experience . Auditory figure-ground plays a role in diminishing sounds which are not important while focusing on others -LSB- 10 -RSB- . It is due to this component that someone can listen to another person talking in a railway station , where a lot of environmental noise exists . Material and methods The medline research revealed 564 papers when using the keywords ` auditory deficits ' and ` mental disorders ' . 79 papers were referring specifically to CAPD in connection with mental disorders , as this is a new term for auditory deficits and one mostly used by audiologists . Auditory deficit is a more general term used mostly by psychiatrists . Both terms refer to the same disorder . It is essential to point out that 25 of the 79 papers are published between 2000 -- 2003 . Schizophrenia is found related to CAPD in 175 papers , 49 of them are published between 2000 -- 2003 showing the research focus of the last three years . Learning disabilities were found related to CAPD in 126 papers . Parkinson 's disease was related to CAPD in 29 papers . Dyslexia is related to CAPD in 88 papers , 37 of them are between 2000 -- 2003 . Alzheimer 's disease and auditory deficits are connected in 39 papers . The remaining articles are on depression , alcoholism , anorexia and childhood mental retardation , all being related to some extend to CAPD . Assessment of the CANS is carried through a great variety of tests that fall into two main categories : psychoacoustic and electrophysiologic testing . Psychoacoustic tests are considered more subjective . Electrophysiologic ones are more objective with the exception of P300 component . Results psychoacoustic tests Learning disabilities , attention deficit disorders and dyslexia are assessed through a great variety of psychoacoustic tests . Age limitations have to be considered -LSB- 11 -RSB- and specially designed tests are used for different age groups . When evaluating children who are less than 12 years old an important step is the Pediatric Speech Intelligibility -LRB- PSI -RRB- Test . This consists of single words and sentences presented with a competing message at varying levels of difficulty -LSB- 12 -RSB- . In this test it is essential that performance is adjusted for language age according to previously determined normative data -LSB- 13 -RSB- . Evaluation of this test may provide the cause of learning disabilities including dyslexia -LSB- 14,15 -RSB- . Children older than 12 years old are assessed through a more complex test battery that contains several tests . These tests are based on the stimulation of the auditory system with tones , numbers , syllables , words and sentences . Evaluation is made according to the different components of the auditory processing . One widely used test is that of the dichotic digits which consists of different pairs of numbers presented simultaneously to each ear -LSB- 16 -RSB- . The person under examination has to repeat all four numbers regardless of order . This test is easy to use in order to detect the auditory deficit of dyslexia particularly since it does not contain language and phonological parameters -LSB- 17 -RSB- . The Staggered Spondaic Word Test -LRB- SSW -RRB- consists of two-syllable spondaic words that are presented simultaneously to each ear -LSB- 18 -RSB- . This involves the diagnosis of auditory deficits in attention disorders , autism , learning disabilities and chronic alcoholism -LSB- 19,20 -RSB- . A series of experiments were planned by Nielzen and Olsson on the basis of psychoacoustic handling of auditory stimulation . The results of these psychacoustic experiments show significant differences between a group of schizophrenic patients and a group of reference subjects thus indicating central auditory processing disorders even in a phase of illness remission or during treatment with neuroleptics -LSB- 21 -RSB- . electrophysiologic tests In all mental disorders assessed with the suspicion of CAPD an objective measure of the peripheral auditory system is mandatory . The Auditory Brainstem Responses -LRB- ABR -RRB- , measure the electrophysiologic activity from the 8th cranial nerve to the medial geniculate body of the brainstem -LSB- 22 -RSB- . A very important element of ABR evaluation is the morphology and synchronization of the waveform . One should always begin his evaluation while observing waveform changes on real time -LSB- 23 -RSB- . The Auditory Middle Latency Responses -LRB- AMLRs -RRB- provide an electrophysiologic measure of the primary auditory cortex function -LSB- 24 -RSB- . The AMLRs can diagnose central auditory processing disorders in children with learning disabilities -LSB- 25 -RSB- , patients with Alzheimer 's disease -LSB- 26 -RSB- , adult autistic subjects -LSB- 27,28 -RSB- patients with Schizophrenia -LSB- 29 -RSB- The Auditory P300 Response , which consists of the measure of the hippocampal and auditory cortex function again from an electrophysiological point of view -LSB- 30 -RSB- . The P300 response has been considered an endogenous event-related potential . Endogenous responses depend both on the context within which the auditory stimuli are presented and the psychologic condition and attention of the subject . P300 has been used in diagnosing CAPD in patients with dementia of the Alzheimer type -LSB- 31 -RSB- , in monitoring long-term effects of donepezil in patients with Alzheimer 's disease -LSB- 32 -RSB- , in anorexic patients -LSB- 33 -RSB- , in children with mental retardation during a selective attention task to auditory stimuli -LSB- 34 -RSB- and in first episode and chronic schizophrenia -LSB- 35 -RSB- . Mismatch Negativity Response -LRB- MMN -RRB- is an event-related evoked potential that measures the electrophysiologic activity of the auditory cortex function -LSB- 36 -RSB- . The MMN is always elicited 100 -- 250 msecs from stimulus change onset . Its application is in detecting CAPD in alcoholism -LSB- 37 -RSB- , in Schizophrenia -LSB- 38-43 -RSB- , in attention deficit and in developmental dyslexia -LSB- 44 -RSB- . psychoacoustic and electrophysiologic testing according to type of lesion In the selection of tests for the evaluation of brainstem lesions the examiner should keep in mind that all psychoacoustic tests have been reported to aid in the diagnosis . According to the studies of Kartz -LSB- 45 -RSB- the Staggered Spondaic Words Test may help differentiating brainstem from cortical lesions and upper from lower brainstem lesions . Musiek et al -LSB- 46 -RSB- concluded that Auditory Brainstem Responses in combination with either Masking Level Differences or Dichotic Digits Test may be as sensitive in evaluating a group of patients suffering from multiple sclerosis as a seven test battery . Jerger et al -LSB- 47 -RSB- reported that for patients suffering from multiple sclerosis the best test battery was a combination of stapedial reflex measures and speech audiometry . The usual finding in central auditory tests regarding cortical lesions is a deficit or impairment in the ear contralateral to the side of lesion . Psychoacoustic tests such as Dichotic Digits and SSW in patients with well documented cortical and hemispheric lesions demonstrate primarily contralateral ear deficits and impairments -LSB- 48 -RSB- . Two exceptions that the examiner should always keep in mind are when frequency and duration tests are applied and when compromise of auditory fibers of the corpus callosum has occurred -LSB- 49 -RSB- . Regarding interhemispheric dysfunction , test results may be difficult to evaluate . Representation of auditory information at the cortical level is mostly contralateral as is clearly depicted in dichotic listening situations . When speech responses are required by the subject auditory information from the right ear are projected through to the left hemisphere without the participation of the opposite hemisphere for the production of a speech response . On the contrary auditory stimuli from the left ear must cross the midline through the corpus callosum for the production of a speech response . Patients with split brain disorders subjected to dichotic testing have interestingly demonstrated decreased scores regarding the left ear and enhanced scores in the right ear -LSB- 50,51 -RSB- . Considerable evidence has been reported that indicates a relation between various learning disabilities , including dyslexia , attention deficit hyperactivity disorder and poor performance scores on central auditory tests Learning disabilities in children might be the expression of various underlying central auditory disorders such as maturational , developmental or neurological as depicted by abnormal CAPD test results -LSB- 52 -RSB- . Conclusions CANS assessment represents a fascinating field . Cooperation of professionals in psychiatry , neurology , neuropsychology and pediatric psychology , with the otolaryngologist-audiologist is a prerequisite . Central auditory processing disorders may co-exist with various mental disorders such as : learning disabilities , attention deficit hyperactivity disorder , dyslexia , autism , chronic alcoholism , Alzheimer 's disease , adult autistic disorder , Schizophrenia , anorexia and mental retardation . Assessing these disorders is difficult due to the complex anatomy and physiology of the CANS . This explains the great variety of existing methods of testing with two main categories : those of psychoacoustic methodology and those based on electrophysiologic measures . Physiology of CANS is still not completely understood and further research is needed on development of new tests and validation of their clinical applicability . Conflict of interest none declared

O O B O O O O O O B I O B I I I O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

psychoacoustics
mental disorders
central auditory processing disorders