Abnormal Innate and Adaptive Immunity in Otitis Media

Samples

No. of sample

IgA

IgG

IgM

MEF

586.1 ± 434.6

3033.8 ± 1870.0

617.2 ± 421.2

Serum

644.0 ± 511.3

5948.0 ± 3780.5

1241.5 ± 910.9

Unit: μg/mL measured by radial immunodiffusion as described in referenced study

MEF middle ear fluid

Mucin Dysregulation in Middle Ear Mucosa

Mucins are glycoproteins that are fairly important to the middle ear defense system, thought to be a part of the innate immune system. It was not recognized till recently that the knockout of the mucin gene Muc5b disturbs the function of the Eustachian tube and middle ear and causes acute and fulminant infectious OM [28]. It has been reported that MUC5B is the predominant mucin glycoprotein in chronic otitis media (COM) [29, 30].

Approximately 20 mucin genes have been identified so far. A total of 12 out of 20 mucins have been shown to be in the respiratory tract [12, 13]. However, three to four mucins are identified from the middle ear mucosa; they are MUC5AC, MUC5B, MUC4, and MUC1. Among them, MUC4 and MUC1 are basically membrane-bound mucins, not secretory ones, although they may appear in the middle ear effusion. Only MUC5B and MUC5AC are mucins found in COM [12, 30]. It is known that MUC5B in humans responds to chronic stimuli [30, 31]. Occasionally, MUC5AC may be upregulated in OM [30]. It is clear in the recent studies that MUC5B is the predominant one [12, 13, 29, 30, 32]. MUC5B is actually a mucin expressed in submucosal glands, instead of in the surface epithelia, but it is highly upregulated in COM [29, 31, 32].

It is not clear why MUC5B is highly upregulated, instead of MUC5AC. MUC5AC is expected to be upregulated because it is usually expressed in the epithelial cells including nasopharynx, Eustachian tube, and orifice of the Eustachian tube at the end of the middle ear. Gland-like structures are often observed in chronic OM patients [29, 31].

This observation has been confirmed by in situ hybridization, which shows clearly that MUC5AC positive mucous cells are dominant in the Eustachian tube mucosa whereas MUC5B positive mucous cells are only in the mucous glands of the Eustachian tube and tracheal submucosal glands [12, 13, 31]. In the middle ear mucosa, few MUC5B messenger RNA (mRNA) transcripts are found in the biopsy specimens [29, 32].

These samples are free of COM because they have no history of OM. There are no inflammatory cells infiltrated when examined carefully. MUC5B mucin is a polymer, linked head-to-head. Under a microscope, mucous strings can be found [12, 13, 29, 32]. That is a molecular basis for trapping invading microorganisms.

Advances in Potential Bench to Bedside in OM Research

OM is basically an inflammatory disease. Recent studies indicate that there is an immune suppression issue on the basis of inflammation. The main reason is that some of the inflammatory cytokines and mediators such as IFN-γ and TNF-α are linked to immune responses in the human body. This implies that chronic OM frequently occurs probably due to the immunosuppression in the middle ear mucosa. It appears that Id1 is an important regulatory transcription factor in the regulation of OM propensity. Id1 is linked to the mucin expression in the middle ear epithelial cells, infiltration of δγ T cells in the middle ear mucosa, and the proliferation of the middle ear epithelial cells. These housekeeping roles of Id1 in the middle ear have been recognized in the recent years and play an important role in the innate and adaptive immunity of the middle ear. The essence of Id1 in the middle ear epithelial cells makes it indispensable in the defense of invading microorganisms. Without Id1, the middle ear develops naturally occurring OM with effusion due to weakened innate and adaptive immunity. With too much Id1, the middle ear runs into a status in which predisposition of OM prevails by increasing inflammatory cytokines and mediators.

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