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BACKGROUND. Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic disorder with impaired immunity against intracellular pathogens, such as mycobacteria, attenuated Mycobacterium bovis-Bacillus Calmette-Guérin (BCG) vaccine strains, and environmental mycobacteria, in otherwise healthy individuals. In Mexico, the estimated incidence of tuberculosis in 2019 was 23 cases/100,000 people. BCG vaccination is mandatory in Mexico. PURPOSE. To review the clinical, immunological, and genetic characteristics of MSMD patients followed in ten hospitals across Mexico. METHODS. This retrospective study describes the clinical, immunological, and genetic characteristics of patients in Mexico diagnosed with MSMD from 2006 to 2021. RESULTS. Twenty-two patients from 17 kindreds were diagnosed with MSMD. Fourteen were male (64%) and eight were female. After BCG vaccination, 12 patients (70%) developed BCG infections. Six (22%) developed infections caused by Salmonella, and 11 (50%) developed infections caused by fungi, particularly Histoplasma. Thirteen different pathogenic variants were identified in IL12RB1 (n = 13), IFNGR1 (n = 3), and IFNGR2 (n = 1). Seven of the 22 patients died; the main cause was disseminated BCG infection. CONCLUSION. Interleukin-12Rβ1 deficiency was the main cause of MSMD in the Mexican cohort. The main etiologic agent responsible for morbidity and mortality was BCG.

ANTECEDENTES: Las inmunodeficiencias primarias (IDP) son trastornos genéticos que afectan el sistema inmune. Aproximadamente 85% de los pacientes con IDP requieren terapia con inmunoglobulina. El retraso en el diagnóstico y tratamiento genera complicaciones clínicas y gastos para el sistema de salud.OBJETIVO: Describir la carga económica que representan las IDP tratadas con IG, y comparar el impacto presupuestal antes y después de tratamiento.MATERIAL Y MÉTODOS: Evaluación económica parcial tipo “descripción de costos” y análisis de impacto presupuestal de pacientes con IDP antes y después del tratamiento con IG. El método de recolección y descripción de costos fue mixto: micro-costeo de 37 expedientes seguido de la estimación “descendente” de costos y análisis de impacto presupuestal sobre el cúmulo de 109 casos de pacientes con IDP en seguimiento activo.RESULTADOS: El costo promedio total por infecciones por paciente por año antes de reemplazo con IG fue de $629,299 vs $155,546 tras el inicio de IG, reduciéndose 75%. La neumonía fue la complicación prevenible más costosa y el costo total por infecciones estimado para 109 pacientes antes del diagnóstico fue $ 68.5 millones vs $ 36 millones posterior al inicio de IG. El costo per cápita antes de tratamiento con IG se estimó en $3.96 vs $2.10 posterior al tratamiento.CONCLUSIONES: El diagnóstico y tratamiento oportuno de las IDP con IG disminuye el costo de la atención clínica en $1.87 pesos mexicanos per capita (3.96 vs 2.10 MXN; p < 0.001), representando un impacto presupuestal con ahorro estimado del 47% anual.

Whole-exome sequencing reveals activating STAT1 mutations in some patients with autosomal dominant chronic mucocutaneous candidiasis disease., Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.

A 33 year-old woman presented with numerous 3- to 5-mm red-brown and yellow-brown dome-shaped nodules, primarily located on the scalp, dorsal aspects of the forearms, and lower extremities (Figure 1 and Figure 2). Her lesions started to appear 5 years prior to her consultation with increasing number and without spontaneous regression. Findings from a previous biopsy revealed epithelioid dermatofibroma. The remainder of the physical examination was unremarkable. There were no familial cases of this condition (both the mother and two older sisters were examined).

Primary immunodeficiencies are rare immunologic diseases whose main characteristics are recurrent infections. These diseases are frequently unsuspected and the delayed diagnosis makes complications irreversible with the consequent poor quality of life. In Mexico, primary immunodeficiencies have a low prevalence, which is secondary to under-diagnosis and the lack of specialized laboratory studies in most hospitals. Since there is a registration of primary immunodeficiency cases in Europe and other developed countries, it is possible to estimate the incidence of primary immunodeficiencies and to elaborate guidelines of diagnosis and treatment. In our country we do not have any epidemiological registry; however, from 1998 to 2004 the number of cases of primary immunodeficiency has increased; the minimal incidence calculated is 0.16 to 0.24 per 100,000 births for chronic granulomatous disease, severe combined immunodeficiency and X linked agammaglobulinemia, this data is still very low compared to other international registries. We present an epidemiological review of primary immunodeficiency prevalence in Mexico compared to some international reports.

The chronic granulomatous disease is a primary immunodeficiency with a defect of the phagocytosis process; its main alteration resides in the incapacity of the NADPH oxidase system to produce reactive oxygen species capable of destruct pathogenic organisms such as bacteria, fungus and mycobacteria. Patients are susceptible to severe and mild infections, mainly pneumonias, linfadenitis and gastroenteritis that tend to be repetitive; in addition, they presented granulomatous inflammation and autoimmunity. We presented the case of two brothers with X-linked chronic granulomatous disease with alteration in the sub-unit gp91Phox; heredofamilial background was endogamy and consanguinity. Both patients suffered severe infections, frequent abscesses and a poor growth. Diagnosis was confirmed with nitroblue tetrazolium test. During their evolution, the patients presented also BCGitis, BCGosis and septic shock. They began prophylactic treatment with trimetoprim sulfametoxazole and itraconazole, as well as gamma interferon, with favorable response, presenting a lower amount of infectious episodes, as well as a recovery of their weight and height. The early diagnosis of the patients has improved their prognosis.

Polyarteritis nodosa is a diffuse vasculitis of small- and medium-sized muscular arteries that can involve the vessels of one or several organ systems. We report an 11-year-old boy with severe atopic dermatitis further complicated with erythroderma and cerebellar symptoms. Laboratory studies showed negative antinuclear antibodies and antineutrophil cytoplasmic antibodies; increased serum complement, IgG cryoglobulins 96.8 mg/dL (0-80) and serum IgG 2,160 mg/dL (613-1,295), and positive alpha-cardiolipin test. The IgE value was high. Skin prick tests and RAST were positive for dust mites and casein. The viral profile was negative. Imaging studies disclosed tortuousity in the vessels and ischemic infarction in the cerebellum and thalamus. A diagnosis of polyarteritis nodosa with central nervous system involvement was made. The patient improved with immunosuppressive therapy and thalidomide. Currently, the patient is controlled and in a rehabilitation program. Other cases of polyarteritis nodosa associated with atopic dermatitis have not been reported.

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency due to mutations in the gene encoding Bruton’s tyrosine kinase (Btk). Btk is a key protein in the B cell receptor signaling pathway. Functional characterization of the mutated Btk in patients with XLA is important in order to define that they are disease causing mutations. Previously, we identified two novel missense mutations in Btk in XLA patients. Using in silico assays we determined that L111P and E605G produced modifications in the structural conformation, affecting the protein organization and its functionality. The absence of catalytic activity of Btk from the patients was reflected on the lack of the Y223 phosphorylation, lack of calcium release and aberrant Btk redistribution after BCR crosslinking. This work shows for that the L111 and E605 residues are fundamental for the activation and functionality of the Bruton’s tyrosine kinase. Additionaly, in silico analysis can be a useful tool for understanding Btk mutations found in primary immunodeficiency patients.

Mendelian susceptibility to mycobacterial disease (MSMD) is a heterogenous syndrome. The clinical characteristics include repetitive local infection and in some cases dissemination. In this work we analyzed a 5 years old boy with an uncharacterized mycobacterial infection. His parents are first degree cousins. Blood samples were collected and cultured 48 hours with medium, BCG or BCG+IL-12. Supernatants were assayed for IFN-γ by ELISA. PBMC were cultured with PMA-Ionomicyn and IL12R was measured by flow cytometry. We found low production of IFN γ after stimulation with BCG+IL12 that seems to correlate with an IL-12R defect. Flow cytometry showed a decrease of IL-12RB1 expression. Sequencing revealed a point mutation (A182T), which generates E61G change in the extracellular domain. Furthermore, the uncommon clinical features in this case might suggest another primary immunodeficiency.

Although various mechanisms involving antibodies and various cell types participate, a Thl and Th2 cells imbalance seems to play a central role for allergy development. Other lymphocyte subpopulations, such as Th17, CD4 FOXP3, and Th9 positive regulatory T lymphocytes may also be involved in the allergic response. Regulatory processes are an appealing target for therapeutic approaches aiming to solve allergic reactions by restoring the delicate balance within the immune system. Transfer factor (TF) or dialyzable leukocyte extract is meant to transfer cell-mediated immunity from immune competent donors to unsensitized or deficient recipients. A PubMed search on the current knowledge on TF indicates that TF may restore the Th1/Th2 balance and improve immune regulatory mechanisms of patients receiving it. Our preliminary results demonstrate that TF induces mRNA expression of IFN-g, osteopontin, RANTES, and hBD-2 in human healthy subjects. TF has been used to treat a variety of immune dysfunction related-pathologies, such as allergy, autoimmunity, immunodeficiencies, infectious diseases and tumors. Patients receiving TF together with their conventional treatment often have better clinical evolution than without it, as we have witnessed, adding TF to the usual medical treatment of allergic diseases as an attempt to provide allergic patients with those regulatory elements that they apparently lack but require to achieve properly regulated immune responses and thus obtain a faster and better resolution of allergic reactions.