The report of the 2003 meeting of the IUIS Scientific Committee for Primary Immunodeficiency Diseases (PID) has been published recently in the Journal of Allergy and Clinical Immunology [1]. As before [2], this takes the form of updated tables related to the text produced in 1999, with the welcome addition of new tables; in particular, genetically inherited auto-inflammatory disorders − the periodic fevers are included, and there are significant updates to the tables of autoimmune lymphoproliferative syndromes, defects of innate immunity and complement deficiencies (published last in 1999). These additions improve the overall classification of defects of the immune system and their various roles in causing human immunological disease.
Classification of these defects continues to be in relation to cells affected, in either number or function. Tables are presented according to the clinical as well as the cellular phenotype of the disorders, namely:
Table 1: Severe combined immune deficiencies: T-B– or T-B+, listing the specific deficiencies which result in this severe clinical phenotype.
Table 2: Predominantly antibody deficiencies − those B cell defects that usually present as recurrent bacterial infections, whether or not they are due to single gene defects.
Table 3: Other well-defined immunodeficiency syndromes in which there are non-immunological features. This section includes syndromes with defects in DNA repair mechanisms.
Table 4: Diseases of immune dysregulation, including defects of apoptosis resulting in lymphoproliferative or autoimmune syndromes.
Table 5: Congenital defects of phagocytic cells, including neutropenia and functional defects of neutrophils and monocytes.
Table 6: Defects of innate immunity relating to monocyte and dendritic cell functions.
Table 7: Autoinflammatory disorders, classifying the periodic fevers.
Table 8: Complement deficiencies.
The predominant clinical features of each condition has led in the past to the discovery of the cellular nature of the affected cells, and hence to the underlying genetic defects in these cells. In the same way as these findings have helped to unravel the physiology of the normal immune system, so the understanding of the molecular defect in an affected cell type had led to improved clinical understanding and patient management. Coupled with an increasing number of patients being diagnosed, due to improved ascertainment, the entry of detailed information (including clinical outcome) to disease and mutation specific registers has led to a greater understanding of the clinical significance of the mutations. The lack of a clear genotype : phenotype correlation in single gene disorders has given further insights to potential mechanisms, as well as the need to search for both regulatory and disease-modifying genes.
Particular additions to the classification in 2004 are mentioned below. Mutations in relation to DNA ligase IV and CD3δ deficiencies have been added to the list of causes of severe combined immunodeficiencies (Table 1). The wider spectrum of hyper-IgM syndromes now includes those deficiencies of activation-induced cytidine deaminase (AID) and uracil-DNA glycosylase (UNG), as well as CD40 and CD40L deficiencies. Because the clinical as well as the immunological phenotypes of these newest hyper-IgM syndromes seem to differ from those of the CD40 : CD40 ligand defects, the new ones are included in antibody defects (Table 2), rather than as T + B combined deficiencies. Similarly, mutations in the inducible co-stimulator (ICOS) gene are associated with B cell deficiencies and have been added to Table 2.
The immune defects associated with non-immunological features such as Wiskott–Aldrich syndrome, DNA repair defects and thymic defects, have traditionally been classified together. This group has included Bloom syndrome, so the helicase gene mutation in this syndrome has been added to Table 3. Diseases of immune dysregulation have been found in patients with symptoms of immune deficiency as well as autoimmunity, and so these have been grouped together in Table 4. In due course, those due to defects in apoptosis resulting in autoimmune lymphoproliferative syndromes may well form a distinct table of their own, as may those of regulatory transcription factors.
The table of phagocytic disorders, which relates to numbers and functions of neutrophils and monocytes (Table 5), has been expanded considerably. The addition of leucocyte adhesion deficiency (LAD) type 3, Rac 2 deficiency, β actin deficiency and localized juvenile periodontitis extends the spectrum of defects, from those of wound healing or localized infections to severe clinical phenotypes requiring bone marrow transplantation.
There is a new table of other innate immunity deficiencies (Table 6); this is predominantly signalling defects. It also includes the new complement-related deficiencies −mannose binding protein (MBP) deficiency and MBP-associated serine protease 2 (MASP2) deficiency although these diseases also feature in the complement deficiencies table (Table 8).
The new tables, and the regrouping of diseases into an increasingly logical framework, provide practical help for clinicians. The Committee took the decision to include the periodic fevers in the PID classification, as patients with these syndromes often present in PID clinics with symptoms similar to the more traditional PIDs. Their inclusion here should help when considering the differential diagnoses of an individual patient. The addition of more subheadings within existing tables for clarity, as more diseases are added to the classification, is essential.
Over the years many developments in basic immunology have been suggested by the findings in PIDs [3,4]. More recently immune defects in knock-out mice have led to the discovery of novel human PIDs [5,6], although the species differences and resulting variance in clinical phenotype has been disappointing [7–9]. The increasing list of mice with immune defects resulting from mutagenesis studies suggests strongly that new PIDs will continue to be described [10].
The next meeting of the IUIS Scientific Committee for PID is to be held in the summer of 2005 in Hungary. No doubt more PIDs will have been reported by then, leading to a better understanding of the clinical phenotypes and immunopathogenic mechanisms in existing as well as new disorders. This, in turn, will result in continuing improvements in the diagnosis of and treatment for PIDs. Many national and international groups are continuing to produce diagnostic guidelines, based on these advances. Such guidelines increase awareness of PIDs among non-immunology specialists as well as providing a means of standardizing diagnostic methods and sharing good practice. The IUIS reports continue to be a firm basis for such revisions and themselves help to increase the profile of PIDs around the world.
