Page 540 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 36 Immunodeficiencies at the Interface of Innate and Adaptive Immunity 519

were S. aureus in 53% of patients, S. pneumoniae in 20% of
patients, and P. aeruginosa in 13% of patients. Most patients with HOIP Deficiency
MyD88 deficiency have had noninvasive bacterial infections, with AR HOIP (HOIP is also known as RNF31, OMIM 612487)
half of the patients suffering from their first noninvasive bacterial deficiency caused by a homozygous mutation has also been
infection before the age of 2 years. Patients with MyD88 deficiency identified in one patient. This patient displayed an autoinflam-
continue to suffer from skin infections, sinusitis, or pneumonia, matory syndrome, pyogenic bacterial diseases, amylopectinosis,
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even after reaching adolescence. Treatment recommendations and lymphangiectasia. At the cellular level, HOIP deficiency
for patients with MyD88 deficiency are identical to those for causes the same impaired responses to TNF and IL-1β agonists
those with IRAK-4 deficiency (see above). A diagnosis of MyD88 found in patients with AR HOIL-1 deficiency. Systemic inflam-
deficiency should be considered in children presenting with mation results from the overactivation of monocytes in response
recurrent pyogenic infection with poor inflammatory responses. to stimulation with IL-1β. Immunological investigations showed
T-cell lymphopenia, an impaired proliferative response to
THEraPEuTIC PrINCIPLES anti-CD3, and hypogammaglobulinemia associated with non-
Treatment of Patients with HSE Susceptibility protective antibody responses to S. pneumoniae and H. influenzae,
but with a good antibody response to tetanus toxoid. In addition
• Treatment with interferon (IFN)-α, in parallel with acyclovir, may help to recurrent autoinflammation, this patient developed generalized
to improve disease outcome in patients with Toll-like receptor 3 (TLR3) lymphadenopathy after immunization with BCG. She also had
pathway deficiencies, in particular. recurrent episodes of diarrhea, amyotrophy, muscle weakness,
• Serological monitoring for herpes simplex virus 1 (HSV-1) infection and failure to thrive, partly because of muscle amylopectinosis.
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should be considered in individuals carrying mutations of TLR3 pathway
genes but with no anti-HSV-1 antibody detectable in serum. Patients with HOIP deficiency should be treated in the same
• In the absence of an effective vaccine against HSV-1, acyclovir may way as those with HOIL-1 deficiency.
be considered an appropriate prophylactic treatment in individuals
carrying mutations of TLR3 pathway genes, even if serologically negative GENETIC DISORDERS OF
for HSV-1.
TH17-MEDIATED IMMUNITY
CMC is characterized by persistent or recurrent infections of
HOIL1 Deficiency skin (intertrigo, angular cheilitis), mucous membranes (oral,
The linear ubiquitination chain assembly complex (LUBAC) is esophageal, genital), and nails (onychomycosis) caused by Candida
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assembled by a complex containing HOIL1 (also known as (C. albicans in particular). CMC was first described in the 1960s
RBCK1), SHARPIN, and HOIP (also known as RNF31). LUBAC and was reported to display AD heritance. Isolated CMC usually
adds head-to-tail linear polyubiquitin chains to substrate protein begins early in infancy and affects otherwise healthy individuals.
and has been implicated in NF-κB signaling, together with NEMO, Invasive candidiasis, dermatophytosis, bacterial infections of the
RIPK1, and ASC1. AR HOIL1 (HOIL1/RBCK1, OMIM# 610924) respiratory tract, and cutaneous infections caused by Staphylococ-
deficiency, caused by homozygous or compound heterozygous cus have been reported in some patients. In rare cases, an associa-
mutations of the HOIL1 gene, has been identified in three patients. tion with cerebral aneurysm or oral/esophageal squamous cell
These patients had a paradoxical clinical phenotype combining carcinoma, and thyroid autoimmunity has also been described.
an autoinflammatory syndrome with pyogenic bacterial diseases, These PIDs are caused by mutations of the IL17RA, IL17RC,
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which led to their death. LUBAC deficiency results in an impaired IL17F, ACT1, and STAT1 genes (Fig. 36.6). 17-20 Some patients
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response to TNF and IL-1β in fibroblasts or to CD40L in B cells, with invasive candidiasis carry mutations of the CARD9 gene.
but hyperresponsiveness to IL-1β in monocytes. All three patients The molecular and clinical features of CMC have been reviewed
had recurrent systemic inflammatory symptoms, present from elsewhere. In particular, this condition is reported in patients
the first few months of life, as a result of monocyte overactivation. with AR autoimmune polyendocrinopathy syndrome type 1
They also developed recurrent pyogenic bacterial infections caused (APS-1 or APECED) (OMIM 240300). APS-1 is caused by
by S. pneumoniae, H. influenzae, Escherichia coli, Staphylococcus mutations of the AIRE gene resulting in impaired T-cell tolerance,
spp., and Enterococcus, partly because of their inability to produce with 88% of patients developing CMC. High levels of neutralizing
antipolysaccharide antibodies. One patient also had chronic CMV autoantibodies against IL-17A, IL-17F, and/or IL-22 have been
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infection and another had Giardia intestinalis infection. All detected in the serum of patients with APS-1. 50
three patients also had amyotrophy, muscle weakness, and failure AR complete IL-17RA deficiency (OMIM 613953) was first
to thrive, partly as a result of muscular amylopectinosis com- identified in 2011 (see Fig. 36.6). A patient from a consanguineous
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plicated by myopathy and cardiomyopathy. More recently, 14 family from Morocco was found to suffer from recurrent CMC
patients with HOIL1 deficiency from 10 unrelated kindreds have (resistant to local antifungal treatment), cutaneous abscesses
been reported, with identification on the basis of neuromuscular and folliculitis caused by S. aureus, acute otitis media, and lower
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and cardiac involvement secondary to amylopectinosis. Patients respiratory tract infections. No invasive bacterial infectious
with HOIL1 deficiency should be immunized (with S. pneumoniae disease was reported in this patient. A homozygous premature
conjugated and nonconjugated vaccines, H. influenzae conjugated stop codon was found to prevent production of the protein in
vaccine, and N. meningitidis conjugated and nonconjugated this patient. The cellular phenotype was characterized by an
vaccines). Prophylactic penicillin V treatment and IgG substitution absence of response to IL-17A and IL-17F homo- and heterodi-
17
should also be considered. Heart transplantation should be mers and to IL-17E (IL-25), in the patient’s fibroblasts. Seventeen
considered for patients with heart failure. The autoinflammation other patients from nine unrelated kindreds have since been
is more difficult to control. One patient underwent HSCT, which identified (Puel A).
corrected the autoinflammation and the predisposition to infec- AD IL-17F deficiency (OMIM 613956) was also first described
17
tious disease. in 2011 (see Fig. 36.6). Patients from a multiplex kindred from